微生物学报

NAKs members	Substrate proteins	Modification sites	Physiological functions	Related diseases
AAK1	AP2M1	T156	Regulation of CME^[45]; endosomal pathway^[46]; receptor-mediated endocytosis^[46]; receptor endocytosis and recycling^[21,47-50]; angiogenesis^[47]; regulation of the Wnt signaling pathway^[59]; coated vesicle cycle^[128]; regulation of protein subcellular localization^[129-130]; apoptosis^[8,51-52]; clathrin-coated pit (CCP) formation and cargo sorting^[131]; caspase-11-dependent pyroptosis^[53-54]; macroautophagy/autophagy^[9,34-35]	AD^[4]; impairment of learning and memory^[130]; vascular dementia^[129]; colon adenocarcinoma^[8]; breast cancer^[9]; bladder urothelial carcinoma^[10]; gastric cancer^[11]
	Numb	T102	Regulation of the Notch signaling pathway^[132]; coated pit maturation^[44]	-
	Eps15	-	Coated pit maturation^[44]	-
	IκBα	S536, K310	Regulation of the NF-κB signaling pathway^[53]	Ischemic stroke^[133]; pulmonary inflammatory^[53]
	Notch 1	-	Regulation of the Notch signaling pathway^[57]; promoted neural stem cell differentiation^[58]	Ischemic stroke^[58]
	REPS1/2, RALBP1	-	Epithelial-mesenchymal plasticity^[12]; increased therapy resistance^[12]	Hepatocellular carcinoma^[12]
GAK	Hsc70	-	Coated pit maturation^[134]	-
	Cyclin G	-	Regulation of cell-cycle^[74]	-
	TAp63	T46, T281	Tumorigenesis^[92]	-
	N-AChE-S	-	Apoptosis^[5]	AD^[5]
	IL12β a2	-	Cell signaling^[85]	-
	AR	-	Cell signaling^[13]	Prostate cancer^[13]
	Vha44	S543	Lysosomal acidification^[7]	PD^[6-7]
	AP2M1	T156	Regulation of CME^[135]; cell growth and centrosome duplication^[136]; endosomal pathway^[78]	-
	AP1	-	Receptor-mediated endocytosis^[82]; golgi to lysosome transport^[78,80]	-
	Atp1a3	T705	Resting membrane potential^[84]	PD^[84]
	Sipa1L1	T249	Brain developmental regulation^[84]	-
	CHC	T606	Regulation of mitosis^[89,137]	-
	PP2A	T104	Microtubule generation and outgrowth^[91]	-
	LRRK2	-	Regulation of neuron projection development^[138]	PD^[138]
BMP2K	AP2M1	T156	Regulation of CME^[98]	-
	CLINT1	T294	Sorting in TGN-endosome pathway^[31]	-
	ACKR3	-	Regulation of the GPCR signaling pathway^[102]	-
	CDK2	-	Polyploidization^[112]; regulation of bone mineralization^[107]	Osteoporosis^[107]; megakaryoblastic leukemia^[112]
STK16	DRG1	T100	Cellular growth^[119]	-
	STAT3	S727	Drug resistance^[14]	Triple-negative breast cancer^[14]
	c-MYC	S452	Ubiquitin-proteasome pathway^[15]	Colorectal cancer^[15]
	WDR1	-	Hepatic secretion^[122]	-
	AKT1	-	Regulation of AKT1 pathway^[16]; cell proliferation and apoptosis^[16]	Lung adenocarcinoma^[16]
	CNP/VEGF	-	Regulation of the TGF-β signaling pathway^[139]	-
	ELK1	-	Cell signaling^[123]	Brain lower grade glioma^[123]

NAKs members	Substrate proteins	Modification sites	Physiological functions	Related diseases
AAK1	AP2M1	T156	Regulation of CME^[45]; endosomal pathway^[46]; receptor-mediated endocytosis^[46]; receptor endocytosis and recycling^[21,47-50]; angiogenesis^[47]; regulation of the Wnt signaling pathway^[59]; coated vesicle cycle^[128]; regulation of protein subcellular localization^[129-130]; apoptosis^[8,51-52]; clathrin-coated pit (CCP) formation and cargo sorting^[131]; caspase-11-dependent pyroptosis^[53-54]; macroautophagy/autophagy^[9,34-35]	AD^[4]; impairment of learning and memory^[130]; vascular dementia^[129]; colon adenocarcinoma^[8]; breast cancer^[9]; bladder urothelial carcinoma^[10]; gastric cancer^[11]
	Numb	T102	Regulation of the Notch signaling pathway^[132]; coated pit maturation^[44]	-
	Eps15	-	Coated pit maturation^[44]	-
	IκBα	S536, K310	Regulation of the NF-κB signaling pathway^[53]	Ischemic stroke^[133]; pulmonary inflammatory^[53]
	Notch 1	-	Regulation of the Notch signaling pathway^[57]; promoted neural stem cell differentiation^[58]	Ischemic stroke^[58]
	REPS1/2, RALBP1	-	Epithelial-mesenchymal plasticity^[12]; increased therapy resistance^[12]	Hepatocellular carcinoma^[12]
GAK	Hsc70	-	Coated pit maturation^[134]	-
	Cyclin G	-	Regulation of cell-cycle^[74]	-
	TAp63	T46, T281	Tumorigenesis^[92]	-
	N-AChE-S	-	Apoptosis^[5]	AD^[5]
	IL12β a2	-	Cell signaling^[85]	-
	AR	-	Cell signaling^[13]	Prostate cancer^[13]
	Vha44	S543	Lysosomal acidification^[7]	PD^[6-7]
	AP2M1	T156	Regulation of CME^[135]; cell growth and centrosome duplication^[136]; endosomal pathway^[78]	-
	AP1	-	Receptor-mediated endocytosis^[82]; golgi to lysosome transport^[78,80]	-
	Atp1a3	T705	Resting membrane potential^[84]	PD^[84]
	Sipa1L1	T249	Brain developmental regulation^[84]	-
	CHC	T606	Regulation of mitosis^[89,137]	-
	PP2A	T104	Microtubule generation and outgrowth^[91]	-
	LRRK2	-	Regulation of neuron projection development^[138]	PD^[138]
BMP2K	AP2M1	T156	Regulation of CME^[98]	-
	CLINT1	T294	Sorting in TGN-endosome pathway^[31]	-
	ACKR3	-	Regulation of the GPCR signaling pathway^[102]	-
	CDK2	-	Polyploidization^[112]; regulation of bone mineralization^[107]	Osteoporosis^[107]; megakaryoblastic leukemia^[112]
STK16	DRG1	T100	Cellular growth^[119]	-
	STAT3	S727	Drug resistance^[14]	Triple-negative breast cancer^[14]
	c-MYC	S452	Ubiquitin-proteasome pathway^[15]	Colorectal cancer^[15]
	WDR1	-	Hepatic secretion^[122]	-
	AKT1	-	Regulation of AKT1 pathway^[16]; cell proliferation and apoptosis^[16]	Lung adenocarcinoma^[16]
	CNP/VEGF	-	Regulation of the TGF-β signaling pathway^[139]	-
	ELK1	-	Cell signaling^[123]	Brain lower grade glioma^[123]

NAKs members	Viruses	Substrate proteins of NAKs	Stage(s) of the viral life cycle involved	Inhibitors	References
AAK1	HPV	-	Immune evasion	-	[143]
HCV	AP2M1, AP1-A	Entry, assembly, release	Sunitinib	[18-21]
EGFR, Numb, AP2M1	Entry	Sunitinib	[21]
DENV	AP2M1, AP1M1	Entry, release	Sunitinib, Erlotinib	[19,23-25]
EBOV	AP2M1, AP1M1	Entry, release	Sunitinib, Erlotinib	[19,24]
RABV	AP2M1	Entry	Sunitinib	[32-33]
RSV	AP2M1	Immune evasion	-	[56]
SARS-CoV-2	AP2M1	Entry	Baricitinib, 1,2,4a,5-tetrahydro-4H-benzo[b] [1,4]oxazino[4,3-d] [1,4]oxazine scaffold and its derivatives, novel compounds (compounds 12, 11f, and nCorv-EMBS), SGC-AAK1-1-based inhibitors	[36-41,144]
NDV	AP1M1, AP2M1	Assembly/release	Sunitinib, Erlotinib	[145]
TOSV	AP2M1	Entry	Sunitinib	[146]
IAV	AP2M1	Immune evasion	-	[34-35]
LCMV	AP2M1	Immune evasion	-	[34]
PRV	Numb, Notch2	Activation	-	[132]
GAK	HCV	AP2M1, AP1-A	Entry, assembly, release	Sunitinib, isothiazolo[5,4-b]pyridine-based inhibitors	[18,20-22]
DENV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[26-29]
EBOV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[19,26]
CHIKV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[26]
SARS-CoV-2	AP2M1	Entry	RMC-242, Gefitinib, Baricitinib	[36,41]
NDV	AP1M1, AP2M1	Assembly, release	Sunitinib, Erlotinib	[145]
TOSV	AP2M1	Entry	Erlotinib	[146]
BMP2K	DENV	AP2M1, CLINT1	Entry, assembly/release	25A,5Z-7-oxozeaenol	[30-31]
HIV-1	-	Replication	-	[147]
SARS-CoV-2	-	Entry, assembly/release	Sunitinib, Erlotinib, RMC-76	[36]
VEEV	-	-	5Z-7-oxozeaenol	[30]
STK16	SARS-CoV-2	-	Entry, assembly/release	STK16-IN-1	[36]

NAKs members	Viruses	Substrate proteins of NAKs	Stage(s) of the viral life cycle involved	Inhibitors	References
AAK1	HPV	-	Immune evasion	-	[143]
HCV	AP2M1, AP1-A	Entry, assembly, release	Sunitinib	[18-21]
EGFR, Numb, AP2M1	Entry	Sunitinib	[21]
DENV	AP2M1, AP1M1	Entry, release	Sunitinib, Erlotinib	[19,23-25]
EBOV	AP2M1, AP1M1	Entry, release	Sunitinib, Erlotinib	[19,24]
RABV	AP2M1	Entry	Sunitinib	[32-33]
RSV	AP2M1	Immune evasion	-	[56]
SARS-CoV-2	AP2M1	Entry	Baricitinib, 1,2,4a,5-tetrahydro-4H-benzo[b] [1,4]oxazino[4,3-d] [1,4]oxazine scaffold and its derivatives, novel compounds (compounds 12, 11f, and nCorv-EMBS), SGC-AAK1-1-based inhibitors	[36-41,144]
NDV	AP1M1, AP2M1	Assembly/release	Sunitinib, Erlotinib	[145]
TOSV	AP2M1	Entry	Sunitinib	[146]
IAV	AP2M1	Immune evasion	-	[34-35]
LCMV	AP2M1	Immune evasion	-	[34]
PRV	Numb, Notch2	Activation	-	[132]
GAK	HCV	AP2M1, AP1-A	Entry, assembly, release	Sunitinib, isothiazolo[5,4-b]pyridine-based inhibitors	[18,20-22]
DENV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[26-29]
EBOV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[19,26]
CHIKV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[26]
SARS-CoV-2	AP2M1	Entry	RMC-242, Gefitinib, Baricitinib	[36,41]
NDV	AP1M1, AP2M1	Assembly, release	Sunitinib, Erlotinib	[145]
TOSV	AP2M1	Entry	Erlotinib	[146]
BMP2K	DENV	AP2M1, CLINT1	Entry, assembly/release	25A,5Z-7-oxozeaenol	[30-31]
HIV-1	-	Replication	-	[147]
SARS-CoV-2	-	Entry, assembly/release	Sunitinib, Erlotinib, RMC-76	[36]
VEEV	-	-	5Z-7-oxozeaenol	[30]
STK16	SARS-CoV-2	-	Entry, assembly/release	STK16-IN-1	[36]

Numb相关激酶的生理功能及其在病毒感染中的作用

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李睿 ¹ , 蒋艳 ¹ , 游灵巧 ¹ , 孙悦茵 ¹ , 李佳慧 ¹ , 王玉娥 ¹^,²^,^* , 张龙祥 ¹^,^*

微生物学报 | 综述 2026,66(1): 149-169

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微生物学报 | 综述 2026, 66(1): 149-169

Numb相关激酶的生理功能及其在病毒感染中的作用

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李睿¹, 蒋艳¹, 游灵巧¹, 孙悦茵¹, 李佳慧¹, 王玉娥¹^,²^,^*, 张龙祥¹^,^*

作者信息

^1.西南大学动物医学院，重庆

^2.国家生猪技术创新中心，重庆

Numb-associated kinases: physiological functions and roles in viral infection

Rui LI¹, Yan JIANG¹, Lingqiao YOU¹, Yueyin SUN¹, Jiahui LI¹, Yu’e WANG¹^,²^,^*, Longxiang ZHANG¹^,^*

Affiliations

^1.College of Veterinary Medicine, Southwest University, Chongqing, China

^2.National Center of Technology Innovation for Pigs, Chongqing, China

出版时间: 2026-01-04 doi: 10.13343/j.cnki.wsxb.20250587

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摘要

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Numb相关激酶(Numb-associated kinases, NAKs)家族是一类在进化上高度保守的丝氨酸/苏氨酸蛋白激酶，由衔接蛋白相关激酶1 (adaptor-associated kinase 1, AAK1)、细胞周期蛋白G相关激酶(cyclin G-associated kinase, GAK)、骨形态发生蛋白2诱导激酶(bone morphogenetic protein 2-inducible kinase, BMP2K)和丝氨酸/苏氨酸激酶16 (serine/threonine kinase 16, STK16)这4个成员构成。NAKs广泛参与调控细胞的内吞、胞内运输、分化、自噬以及信号转导等基本生命活动。近年来，研究发现NAKs在多种病毒生命周期的不同阶段，包括入侵、组装、释放以及免疫逃逸等环节均发挥着关键作用。同时，已有针对NAKs的小分子抑制剂应用于相关生理性或病毒感染性疾病的临床研究与治疗。本文将系统梳理NAKs的主要生理功能及其在病毒感染中的作用，为病毒致病机制研究和以NAKs为靶点的新药开发提供参考依据。

关键词

Numb相关激酶 / 生理功能 / 小分子抑制剂 / 病毒生命周期

Abstract

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Numb-associated kinases (NAKs) are a family of evolutionarily conserved serine/threonine kinases, encompassing adaptor-associated kinase 1 (AAK1), cyclin G-associated kinase (GAK), bone morphogenetic protein 2-inducible kinase (BMP2K), and serine/threonine kinase 16 (STK16). NAKs are widely involved in various physiological processes, such as endocytosis, intracellular transport, cell differentiation, autophagy, and signal transduction. In recent years, studies have shown that NAKs play a key role in different life cycle stages including virus entry, assembly, release, and immune escape of various viruses. Furthermore, small-molecule inhibitors targeting NAKs have been applied in clinical research and treatment of related physiological or viral infectious diseases. This article systematically reviews the primary physiological functions of NAKs and their roles in viral infection, aiming to provide a theoretical foundation for elucidating the pathogenic mechanisms of viruses and developing novel therapeutic drugs targeting NAKs.

Key words

Numb-associated kinases / physiological function / small-molecule inhibitors / virus life cycle

引用本文

李睿, 蒋艳, 游灵巧, 孙悦茵, 李佳慧, 王玉娥, 张龙祥. Numb相关激酶的生理功能及其在病毒感染中的作用. 微生物学报, 2026 , 66 (1) : 149 -169 . DOI: 10.13343/j.cnki.wsxb.20250587

Rui LI, Yan JIANG, Lingqiao YOU, Yueyin SUN, Jiahui LI, Yu’e WANG, Longxiang ZHANG. Numb-associated kinases: physiological functions and roles in viral infection[J]. Acta Microbiologica Sinica, 2026 , 66 (1) : 149 -169 . DOI: 10.13343/j.cnki.wsxb.20250587

正文

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蛋白激酶是存在于生物体内的一大类酶，根据所涉及的蛋白质种类差异，主要分为酪氨酸激酶和丝氨酸/苏氨酸激酶(serine/threonine kinase, STK)两大类。Numb是一种在进化上保守的多功能蛋白，在细胞命运决定中发挥关键作用，不仅参与细胞内吞、迁移、黏附、分裂等基本细胞活动，还参与蛋白泛素化修饰以及Notch等关键信号通路^[1]。Numb相关激酶(Numb-associated kinases, NAKs)因能磷酸化Numb蛋白而得名，是一类普遍存在于生物体中的丝氨酸/苏氨酸蛋白激酶，该家族现包括4个核心成员：(1) 衔接蛋白相关激酶1 (adaptor-associated kinase 1, AAK1)；(2) 细胞周期蛋白G相关激酶(cyclin G-associated kinase, GAK)；(3) 骨形态发生蛋白2诱导激酶(bone morphogenetic protein 2-inducible kinase, BMP2K)，也称BMP2诱导激酶(BMP2-inducible kinase, BIKE)；(4) STK16，也称MPSK1/PKL12/Krct/TSF-1^[2] (图1A)。结构上，NAKs的N端激酶结构域在进化上高度保守，而C端的其他结构域差异较大，序列同源性低至30%以下^[3] (图1B)。这种“保守头部+多变尾部”的结构特征也决定了其底物的特异性及生理功能的多样性(图1C，红色区域呈现的为NAKs保守的激酶结构域；NAKs高变区分别以紫色、粉色、蓝色和绿色表示)。NAKs通过催化底物蛋白丝氨酸/苏氨酸的磷酸化来发挥其调控功能。目前已鉴定出多种“NAKs-底物”信号轴，为其功能研究奠定了基础。

研究证实，NAKs在参与网格蛋白介导的内吞(clathrin-mediated endocytosis, CME)、调控细胞生长发育、参与细胞自噬体形成与成熟以及介导信号转导调控等生理过程中扮演着重要角色^[2]。NAKs功能异常与多种疾病的进展密切相关，如阿尔茨海默病(Alzheimer disease, AD)^[4-5]、帕金森病(Parkinson’s disease, PD)^[6-7]等神经系统疾病以及胃癌、乳腺癌等多种癌症^[8-16]。值得关注的是，与其他蛋白激酶功能类似，NAKs除了作为细胞生理功能研究的重要靶标外，还可被多种高危的人类或动物病毒利用以完成自身感染^[17]，如丙型肝炎病毒(hepatitis C virus, HCV)^[18-22]、登革热病毒(dengue virus, DENV)^[19,23-31]、埃博拉病毒(Ebola virus, EBOV)^[19,24,26]、狂犬病毒(rabies virus, RABV)^[32-33]、甲型流感病毒(influenza A virus, IAV)^[34-35]和新型冠状病毒(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)^[36-41]等。其中，NAKs可同时参与HCV、DENV、EBOV的入侵、组装和释放，而仅参与RABV和SARS-CoV-2的入侵。鉴于其在生理性和病毒感染性疾病的发生发展中发挥关键作用，NAKs已成为上述疾病的潜在药物开发靶点，如目前用于治疗神经性疼痛的小分子抑制剂舒尼替尼(sunitinib)和LX-9211已被美国食品药品监督管理局批准进入临床^[42-43]。因此，本文将以NAKs激酶家族为切入点，系统梳理该激酶主要的生理功能及其在病毒感染中的作用，为病毒致病机制研究和靶向蛋白激酶的药物设计提供理论框架和策略参考。

1 NAKs的生理功能

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1.1 AAK1

AAK1的生理功能主要涉及调控膜蛋白内吞、参与细胞命运决定、调节细胞信号转导以及参与肿瘤和神经系统疾病的发生发展。

1.1.1 参与膜蛋白内吞

AAK1因可磷酸化Numb蛋白的T102而被归类为NAKs家族^[44]。早期研究发现，它能与衔接蛋白复合体2 (adaptor protein complex 2, AP2)的α亚基结合并磷酸化AP2的μ1亚基(AP2 subunit mu-1, AP2M1)的T156，因此得名衔接蛋白相关激酶1^[45-46]。在CME途径中，AP2M1的磷酸化是启动网格蛋白装配的关键步骤，AAK1通过这一机制调控血管内皮生长因子受体(vascular endothelial growth factor receptors, VEGFR)^[47]、表皮生长因子受体(epidermal growth factor receptor, EGFR)^[21,48]、转铁蛋白受体(transferrin receptor, TfR)^[49]和低密度脂蛋白受体相关蛋白(low density lipoprotein receptor-related protein, LRP)^[50]等多种膜蛋白内吞及后续分选，由此影响血管生成、炎症反应和细胞稳态。此外，AAK1在细胞中的表达量受到精确调控，表达过高反而会抑制内吞^[45,50]。

1.1.2 参与细胞命运决定

细胞命运决定涉及凋亡、焦亡和自噬等多条通路，AAK1在其中发挥关键作用。(1) 凋亡：AAK1介导肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor-related apoptosis-inducing ligand, TRAIL)的内化，抑制癌细胞凋亡^[8]；也可加剧白细胞介素(interleukin, IL)-1β诱导的髓核细胞凋亡与七氟醚诱导的神经元凋亡^[51-52]。(2) 焦亡：通过CME途径促进脂多糖(lipopolysaccharide, LPS)内化，激活Caspase-11触发细胞焦亡^[53-54]。(3) 自噬：其微管相关蛋白轻链3 (microtubule-associated protein light chain 3, LC3)相互作用区(LC3-interacting region, LIR)可与LC3/自噬相关蛋白8 (autophagy-related protein 8, ATG8)结合并被招募至主要组织相容性复合体I类分子(major histocompatibility complex class I molecules, MHC-I)定位的细胞膜处，进而促进MHC-I内化及溶酶体降解^[9,34-35]；同时，也可通过磷酸化AP2M1加速MHC-I自噬清除^[55-56]。

1.1.3 参与细胞信号转导

AAK1通过磷酸化-内吞-降解/活化等方式精细调控以下信号通路。(1) 核因子κB (nuclear factor kappa-B, NF-κB)通路：NF-κB经典通路的激活依赖于核因子κB抑制因子α (inhibitor of NF-κB, IκBα)的磷酸化及泛素化降解，解除对p65/p50二聚体的抑制，促使其入核启动靶基因转录。AAK1可通过促进IκBα降解、催化p65-S536磷酸化及p65-K310乙酰化进一步增强NF-κB活性，从而介导炎症反应并提升细胞存活^[53]。(2) Notch通路：作为该通路的正调控因子，AAK1可与Notch结合并使其内化并在早期内体中保持稳定，进而调控细胞的分化、增殖和凋亡^[57-58]。(3) Wnt通路：LRP6是Wnt配体的共激活受体，AAK1通过CME途径将LRP6内化，阻断其与Wnt配体结合，进而负调节Wnt/β-catenin信号通路的激活^[59]。

1.1.4 AAK1与肿瘤及神经系统疾病密切相关

在肿瘤中AAK1与RalBP1关联的Eps同源结构域蛋白(RalBP1-associated Eps domain-containing protein, REPS) 1/2、RalA结合蛋白1(RalA-binding protein 1, RALBP1)等蛋白相互作用，诱导上皮-间充质转化与耐药^[12]，与胃癌、卵巢癌等预后不良相关^[60-62]。小分子抑制剂Sunitinib (临床试验编号为NCT00510640/NCT00299741)已被用于甲状腺癌和前列腺癌的临床治疗中。在神经系统疾病中AAK1参与神经营养因子内吞^[63]、突触囊泡回收介导的痛觉传递^[64]、神经元迁移与树突塑形^[65-66]，并与AD、PD、家族型肌萎缩性侧索硬化症及青少年重度抑郁症等发病相关^[4,67-69]。抑制剂LX-9211 (临床试验编号为NCT04662281/NCT04455633)在治疗带状疱疹后神经疼痛和糖尿病周围神经疼痛中有显著疗效^[43,70]。除上述功能外，AAK1还参与自然杀伤细胞的功能调节^[71]、调控细胞内的整体翻译水平^[72]以及脂质和活性氧的代谢^[73]。

1.2 GAK

GAK最初因与细胞周期蛋白G结合而被命名为细胞周期蛋白G相关激酶^[74]，又因序列与辅助蛋白(auxilin)高度同源，也称Auxilin 2^[75]。该激酶在胞质和胞核均有分布，胞质GAK对网格蛋白解离和网格蛋白包被的囊泡(clathrin-coated vesicles, CCVs)组装至关重要。它可将热休克同源蛋白70 (heat shock cognate protein 70, Hsc70)招募至CCVs，利用ATP水解驱动网格蛋白晶格解离以完成“解包”；也可结合磷脂协助网格蛋白从囊泡上解离^[76-77]。同时，GAK还可介导网格蛋白与质膜及反式高尔基体网络(trans-Golgi network, TGN)结合^[78]，在CME、受体信号转导及TGN-溶酶体运输中发挥重要作用^[79-81]。值得注意的是，外源过表达GAK反而抑制CME^[82]。GAK通常分别与AP1的γ亚基和AP2的α亚基结合并磷酸化其μ亚基^[75,82]：与AP1结合促进GAK定位于TGN，参与溶酶体酶分选^[83]；与AP2结合则磷酸化AP2M1-T156参与TfR、EGFR等受体内吞^[78]。此外，GAK可磷酸化Na⁺/K⁺-ATP酶α-亚基以调节细胞内的钠钾平衡^[84]，与“突触”乙酰胆碱酯酶变体(N-terminally extended “synaptic” acetylcholinesterase variant, N-AChE-S)结合并抑制其诱导的细胞凋亡^[5]，与IL12受体β2 (interleukin 12 receptor β2, IL-12Rβ2)相互作用调节IL12信号^[85]，并通过维持溶酶体稳态影响线粒体自噬^[86-87]。

核内GAK与cyclin G、蛋白质磷酸酶2A (protein phosphatase 2A, PP2A)、雄激素受体(androgen receptor, AR)、网格蛋白重链(clathrin heavy chain, CHC)和微小染色体维持蛋白3 (minichromosome maintenance protein 3, MCM3)等蛋白结合形成相应的复合物，在调节PP2A和AR的功能活性、维持中心体的成熟、染色体-微管连接及DNA复制许可中发挥重要作用^[13,88-91]。功能异常时GAK通过磷酸化抑癌转录因子含反式激活结构域的p63亚型(transactivation domain-p63 isoform, TAp63)而抑制肿瘤形成^[92]，也能与α-核突触蛋白(α-synuclein)结合参与PD发生发展，并成为潜在治疗靶点^[93-94]。

1.3 BMP2K

BMP2K因最早报道可磷酸化骨形态发生蛋白2 (bone morphogenic protein 2, BMP2)并促进成骨细胞分化而得名^[95]，主要定位于胞质囊泡并以相分离液滴形态存在^[96]。功能上，它与AAK1/GAK相似：通过AP2M1或Numb依赖的CME途径参与EGFR、胰岛素受体底物2 (insulin receptor substrate 2, IRS2)等膜蛋白内吞^[97-101]；与非典型趋化因子受体3 (atypical chemokine receptor 3, ACKR3)相互作用诱导后者磷酸化，参与非经典G蛋白偶联受体(G protein-coupled receptor, GPCR)信号转导^[102]。值得注意的是，BMP2K也可发生缓慢自磷酸化^[95]。

BMP2K与细胞的生长和分化密切相关，且呈细胞类型依赖的双向调控^[103]。抑制成骨细胞分化：可通过影响碱性磷酸酶活性和骨钙素的表达抑制成骨细胞分化^[95,104-105]。促进脂肪细胞分化：长链非编码RNA核富集转录本1 (nuclear enriched abundant transcript 1, NEAT1)可调节BMP2K的表达，促进绵羊前体脂肪细胞分化^[106-107]。促进红细胞成熟：通过调节蛋白转运相关蛋白分泌相关蛋白16同源物(secretory 16 homolog, SEC) A和SEC24B的分布及SEC31A的表达参与红细胞成熟^[108-111]。促进巨核细胞分裂：与细胞周期蛋白依赖性激酶2 (cyclin-dependent kinase 2, CDK2)结合，促进巨核细胞有丝分裂和分化^[112]。此外，临床研究表明，BMP2K与幽门螺杆菌性胃炎^[113]、高度近视^[114]、肥胖^[115]、2型糖尿病^[116]和克氏锥虫感染^[117]，以及白血病、癌症等多种疾病^[100,118]发生发展密切相关。

1.4 STK16

STK16因激酶结构域与NAKs成员相似也被归入本家族，但进化距离较远^[119]。该蛋白的生物学特征先后由Stairs、Kurioka、Ligos和Berson等验证，并曾被命名为Krct、EDPK、PKL12和MPSK1，最终被统一命名为STK16^[120]。目前研究提示其功能可归纳为“激酶+转录因子”双重角色。(1) 激酶活性：STK16可磷酸化发育调控型GTP结合蛋白1 (developmentally regulated GTP-binding protein 1, DRG1)、信号转导和转录激活因子3 (signal transducer and activator of transcription 3, STAT3)、细胞性骨髓细胞瘤病癌基因(cellular myelocytomatosis concogene, c-MYC)、WD重复结构域1 (WD repeat domain 1, WDR1)和丝氨酸/苏氨酸蛋白激酶1 (serine/threonine-protein kinase 1, AKT1)等底物，分别参与调控蛋白泛素化修饰^[121]、Janus激酶(janus kinase, JAK)/信号转导子和转录激活子3 (signal transducer and activator of transcription 3, STAT3)介导的炎症及肿瘤发生^[14]、c-MYC稳定性与细胞周期^[15]、肝细胞的极化与分泌^[122]和细胞代谢及凋亡调控^[16]。(2) 转录活性：STK16可不依赖激酶活性直接结合DNA^[121]，发挥转录因子的作用；可识别转化生长因子-β (transforming growth factor-β, TGF-β)诱导的C型钠尿肽(C-type natriuretic peptide, CNP)和血管内皮生长因子(vascular endothelial growth factor, VEGF)基因近端启动子区中富含GC的调控序列，促进其转录^[120]；也可通过转录因子ETS样蛋白1 (ETS like-1 protein, ELK1)调控基因表达^[123-124]。高尔基体定位的STK16在解聚后转位至核室区，可发挥转录因子功能^[125]。此外，STK16在细胞黏附和乳腺导管形态发生中也发挥重要作用^[121,126]。STK16的上述生理特性为后续深入研究其在平滑肌细胞收缩和极化肝细胞分泌等过程中的作用奠定基础^[122,127]，其异常表达与乳腺癌^[14]、结肠癌^[15]和肺腺癌^[16]等多种癌症密切相关。

1.5 NAKs成员生理功能的区别与联系

NAKs家族“保守头部+多变尾部”的结构特征，决定了其成员在生理功能上既存在相似性，也表现出显著差异性。相似性在于：(1) 除STK16外，所有NAKs成员均可通过磷酸化AP2M1-T156位点或与其他膜蛋白相互作用参与细胞的内吞作用；(2) GAK与STK16进化亲缘关系较近，二者均参与转录调控并与细胞分裂过程相关；(3) 所有4个NAKs成员均参与调控细胞自噬、凋亡和分化等过程，与细胞命运决定密切相关。差异性在于：(1) AAK1：最初因其在神经递质内吞和突触囊泡回收中的作用被视为治疗神经性疼痛的靶点，后续研究揭示其还参与癌症相关受体内吞/循环及多种癌症信号通路调控，使其逐渐成为癌症治疗的潜在靶点；(2) GAK：研究焦点集中于其与PD等神经系统疾病发病机制的关联，同时其在调控细胞有丝分裂中的作用也备受关注；(3) BMP2K：虽与AAK1同源性最高，但其主要功能是调节细胞分化，并参与糖尿病发生和血细胞生成；(4) STK16：作为最新发现的成员，与其他NAKs亲缘关系最远，其功能主要与癌症的发生发展密切相关。为更清晰地阐明NAKs各成员间生理功能的异同点，对其底物、修饰位点以及主要生理/病理功能进行了系统总结(表1)。

2 NAKs在病毒感染中的作用

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前期研究证实宿主细胞蛋白激酶在病毒感染中发挥着重要作用，如PP2A^[140]、EGFR^[141]、TANK结合激酶1 (TANK-binding kinase-1, TBK1)^[142]等宿主细胞蛋白激酶在猪繁殖与呼吸综合征病毒、猪流行性腹泻病毒以及鸭肠炎病毒感染过程中均发挥重要作用。随着对NAKs家族激酶活性研究的深入，近年来多项研究揭示该家族成员在病毒入侵、复制、组装、释放及免疫逃逸等过程中扮演着关键角色(图2)。NAKs与病毒生命周期的对应关系见表2。

2.1 AAK1

AAK1最主要的功能是参与病毒入侵。AAK1是磷酸化AP2M1的关键激酶，该修饰对AP2M1在CME途径中与货物蛋白结合至关重要。包括SARS-CoV-2^[37-41,148]、EBOV^[19]、DENV^[23,25]、HCV^[21]、RABV^[32-33]和托斯卡纳病毒(Toscana virus, TOSV)^[146]等在内的多种病毒，可利用AAK1介导的AP2M1磷酸化，经CME途径进入细胞。例如，在感染过程中DENV和RABV可上调宿主AAK1的mRNA和蛋白水平^[23,33]，进而增强AP2M1磷酸化，促进病毒通过CME途径入侵细胞^[25,32]。靶向AAK1 ATP口袋的抑制剂巴瑞克替尼(baricitinib)、吡咯[2,3-b]吡啶衍生物、SGC-AAK1-1衍生物及化合物(compounds 12、11f和nCorv-EMBS)均可降低AAK1活性，阻断AP2M1磷酸化，阻碍AP2M1与SARS-CoV-2受体血管紧张素转化酶2 (angiotensin-converting enzyme 2, ACE2)的结合，最终抑制病毒入侵^[37-40,148]。此外，AAK1还通过非CME途径参与病毒入侵。如HCV除通过CME途径入侵细胞外，还可借助磷酸化衔接蛋白Numb-T102，经Numb依赖的内吞途径进入细胞；同时，AAK1也可通过增强HCV辅助受体EGFR的内化及再循环，帮助HCV建立有效感染^[21]。

除了参与病毒入侵外，AAK1在病毒组装/释放、潜伏感染解除及免疫逃逸等环节也发挥多重作用。(1) 组装/释放：AAK1通过磷酸化AP2M1促进HCV核衣壳蛋白-AP2M1相互作用，并引导病毒颗粒转运至组装位点完成组装，抑制剂Sunitinib可有效抑制感染性病毒粒子的产生^[19,33]。AAK1还可通过调节AP1和AP4的磷酸化影响其与HCV非结构蛋白2的结合，参与病毒释放及细胞间传播^[20]。抑制AAK1活性或敲低其表达，可减弱AP2M1的磷酸化水平，进而抑制DENV和EBOV的释放^[19,25]。在新城疫病毒(Newcastle disease virus, NDV)中AAK1可磷酸化AP1M1和AP2M1，调控F蛋白的胞内运输及质膜定位，进而影响病毒组装和释放^[145]。(2) 潜伏感染解除：伪狂犬病毒(pseudorabies virus, PRV)感染下调miR-155-5p表达，解除其对AAK1的抑制，导致AAK1表达上调，进而激活Numb/Notch2信号通路，最终促进病毒增殖^[132]。(3) 免疫逃逸：IAV、淋巴细胞脉络丛脑膜炎病毒(lymphocytic choriomeningitis virus, LCMV)和呼吸道合胞病毒(respiratory syncytial virus, RSV)等病毒感染导致细胞的巨自噬增强，LC3B/ATG8表达增加引起AAK1过度被募集，进而促使MHC-I类分子内化与循环，使以上病毒得以逃避宿主免疫防御^[34,56]。此外，AAK1对于人乳头瘤病毒(human papillomavirus, HPV)感染所导致的癌细胞的存活也至关重要，可能与AAK1参与调节多种致癌信号通路以及调节致癌相关受体的内化和循环有关^[143]。

2.2 GAK

GAK和AAK1是最早被鉴定的NAKs成员，常在同一病毒感染中被并行研究。与AAK1类似，GAK通过磷酸化AP2M1介导CME，参与HCV入侵^[21]以及病毒粒子的组装^[18-20]；异噻唑[5,4-b]吡啶、异噻唑[4,3-b]吡啶及其衍生物可靶向GAK ATP口袋，阻断上述过程有效阻止HCV入侵和组装^[22]。此外，GAK还通过相似机制参与TOSV的入侵^[146]以及协助NDV的组装/释放^[145]。靶向GAK的抑制剂异噻唑[4,3-b]吡啶及其衍生物可有效抑制DENV、EBOV和基孔肯雅病毒(chikungunya virus, CHIKV)感染^[26-29]，同时发现结构优化后的衍生物较先导化合物具有更高的靶向性、更低的EC₅₀。GAK抑制剂吉非替尼(gefitinib)、baricitinib和RMC-242等对SARS-CoV-2依赖CME途径入侵宿主细胞具有显著抑制效果，推测其通过抑制GAK-AP2M1轴发挥作用^[36,41]。

2.3 BMP2K和STK16

功能上，BMP2K与AAK1和GAK相似，可磷酸化AP2M1参与CME途径依赖的病毒入侵。研究表明敲除或抑制BMP2K (如新型化合物25A、5Z-7-oxozeaenol)可有效抑制DENV入侵，回补BMP2K可恢复感染水平，提示其对病毒入侵至关重要^[30]。同一抑制剂5Z-7-oxozeaenol也可有效抑制委内瑞拉马脑炎病毒(Venezuelan equine encephalitis virus, VEEV)感染^[30]。敲低BMP2K或使用Sunitinib、Erlotinib和RMC-76等BMP2K抑制剂均可抑制SARS-CoV-2的早期入侵和晚期感染^[36]。此外，BMP2K可磷酸化网格蛋白相互作用蛋白1 (clathrin-interacting protein 1, CLINT1)，磷酸化后的CLINT1可与DENV NS3结合，参与病毒的组装/释放^[31]；敲低BMP2K可抑制HIV的复制，回补后可以拯救这种抑制效果，证实BMP2K作为HIV-1复制所需的关键宿主因子^[147]。

STK16的研究起步较晚，但现有数据表明其同样抑制SARS-CoV-2感染，具体表现为STK16抑制剂STK16-IN-1在病毒的早期入侵和晚期感染阶段均呈剂量依赖性抗病毒效应^[36]，提示STK16也可作为潜在抗病毒靶点。

3 总结与展望

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NAKs是一类进化保守的多功能丝氨酸/苏氨酸激酶，通过直接磷酸化或相互作用等机制调控内吞作用、胞内转运、细胞命运决定、细胞稳态维持和信号转导等关键生理过程。值得注意的是，多种病毒也“劫持” NAKs，利用其对CME关键蛋白的磷酸化或免疫逃逸调控作用完成自身的入侵、复制、组装和释放。然而，目前对于NAKs家族的生理功能认知尚不充分，如新成员STK16的生理功能仍存在诸多谜团。因此，未来的研究亟需：(1) 深入解析NAKs各成员如何协同调控多种信号通路；(2) 系统阐明NAKs在细胞发育、细胞命运决定以及在癌症、神经系统疾病和代谢疾病中的具体作用；(3) 在深入理解NAKs生理功能的基础上，揭示其作为“细胞枢纽”的全局性调控逻辑，为靶向干预或治疗相关疾病奠定理论基础。

在病毒感染领域，尤其是NAKs在病毒感染中的作用及其靶向抑制剂的开发和应用方面虽已取得诸多进展，但仍面临诸多问题。首先，NAKs在病毒生命周期中的具体作用机制仍需深入阐明。其次，针对NAKs的小分子抑制剂的开发、筛选及优化策略仍存在较大难度。病毒建立有效感染常需利用NAKs的生理功能，如某些病毒可借助NAKs介导的膜蛋白内吞和胞内转运过程完成宿主细胞入侵。然而，目前对NAKs家族成员的生理功能研究尚不充分，这也限制了对其在病毒感染中作用机制研究的深度。现阶段，抗病毒药物研发主要聚焦于两大方向：一是靶向病毒的直接抗病毒药物，通过作用于病毒生命周期中的关键环节(如病毒吸附/入侵、基因组转录/复制等)直接抑制或杀灭病毒，代表药物包括病毒吸附/入侵抑制剂、核苷/核苷酸类似物等；二是靶向宿主的间接抗病毒药物，通过作用于宿主细胞中病毒增殖所必需的因子(如病毒受体、宿主蛋白酶、激酶等)干扰病毒生命周期的某个或多个阶段，从而阻断有效感染。该策略的优势在于可能开发出广谱性强且不易诱发病毒耐药性的药物。事实上，鉴于NAKs在多种病毒生命周期的不同阶段发挥关键作用，靶向NAKs的广谱抗病毒抑制剂开发已受到广泛关注并已取得重要进展。例如，在SARS-CoV-2流行期间，NAKs抑制剂Baricitinib被证实可缓解患者由感染引起的临床症状^[40]；NAKs抑制剂Sunitinib也被证实可有效抑制包括HCV、DENV、EBOV、RABV、RSV、NDV、TOSV以及SARS-CoV-2在内的多种病毒的不同感染阶段。然而，目前可用于抗病毒研究或临床治疗的NAKs抑制剂仍然有限。考虑到这类抑制剂显著的广谱抗病毒潜力和广阔的临床应用前景，亟需通过大规模筛选和开发新型药物来满足实际临床需求。

目前，靶向NAKs的抗病毒药物开发策略主要包括老药新用、现有抑制剂优化和新药开发3个方面。(1) 老药新用：典型案例如Sunitinib，该药已从治疗神经性疼痛及癌症转向抗病毒应用。因此，通过高通量筛选已有NAKs抑制剂是否具有抗病毒活性显得至关重要。(2) 现有抑制剂优化：针对Sunitinib、Baricitinib、异噻唑[4,3-b]吡啶等抑制剂存在的细胞毒性大、靶点不专一等问题亟需进行结构优化。例如，通过在异噻唑[4,3-b]吡啶支架的3-苯基或3-哌啶基部位引入羧酰胺残基可获得靶向GAK活性更强、半数抑制浓度(median inhibition concentration, IC₅₀)更低的小分子化合物，该化合物已被证实可有效抑制DENV感染^[28]；通过支架跳跃(scaffold hopping)策略优化鲁索利替尼(Ruxolitinib)和Baricitinib，可获得靶向AAK1选择性更高、疗效更佳的抗病毒化合物^[10]；将SGC-AAK1-1的1H-吲哚唑支架与化合物6的药效团融合，得到的新型化合物11f细胞毒性更低且抗病毒效果与先导化合物相当^[135]。(3) 新药开发：通过基于片段的药物开发(fragment-based drug discovery, FBDD)技术揭示片段9595的卤素键是与AAK1相互作用的关键位点^[149]，这为开发靶向AAK1的新型抑制剂提供了方向；通过化学蛋白质组学(chemical proteomics)技术进行筛选也是重要的新药开发策略之一，如基于TIM-063-kinobeads的化学蛋白质组学筛选出TIM-098a，该化合物可避免脱靶效应，并作为AAK1选择性更高、疗效更优的抗病毒候选物^[135]。此外，还可以考虑多靶点联合策略以提高抗病毒效果，如Mao等^[38]报道了一种同时靶向AAK1和组蛋白去乙酰化酶的新型化合物，能更有效地抑制SARS-CoV-2入侵细胞。

综上所述，未来针对NAKs的研究可重点聚焦于以下两方面：(1) 整合分子生物学、人工智能及多组学等技术手段，系统解析并绘制NAKs-病毒相互作用的全局网络，为临床药物研发奠定理论基础；(2) 持续优化研发策略，开发具有选择性高、毒性低、疗效强的单一或组合抑制剂，并在人类/动物模型中系统评估其安全性与有效性。通过紧密衔接基础研究与临床疾病治疗需求，NAKs有望成为治疗多种生理及病毒感染性疾病的理想靶标，其研究成果也将为深入解析病毒感染机制和推进蛋白激酶靶向药物研发提供重要参考。

基金

收起

国家自然科学基金(32302852)
重庆市自然科学基金(CSTB2023NSCQ-MSX0366)
中央高校基本科研业务费专项资金(SWU-KQ22035)
西南大学大学生创新创业训练计划(S202510635265)
西南大学大学生创新创业训练计划(X202510635250)
重庆市教委科学技术研究项目(KJQN202300224)

参考文献

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2026年第66卷第1期

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文章信息

doi: 10.13343/j.cnki.wsxb.20250587

接收时间：2025-07-29
首发时间：2026-01-12
出版时间：2026-01-04

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出版历史

收稿日期：2025-07-29
录用日期：2025-09-10

基金

National Natural Science Foundation of China(32302852)

国家自然科学基金(32302852)

Natural Science Foundation of Chongqing(CSTB2023NSCQ-MSX0366)

重庆市自然科学基金(CSTB2023NSCQ-MSX0366)

Fundamental Research Funds for the Central Universities(SWU-KQ22035)

中央高校基本科研业务费专项资金(SWU-KQ22035)

Southwest University Training Program of Innovation and Entrepreneurship for Undergraduates Project(S202510635265)

西南大学大学生创新创业训练计划(S202510635265)

西南大学大学生创新创业训练计划(X202510635250)

Science and Technology Research Program of Chongqing Municipal Education Commission(KJQN202300224)

重庆市教委科学技术研究项目(KJQN202300224)

作者信息

^1.西南大学动物医学院，重庆

^2.国家生猪技术创新中心，重庆

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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NAKs members	Substrate proteins	Modification sites	Physiological functions	Related diseases
AAK1	AP2M1	T156	Regulation of CME^[45]; endosomal pathway^[46]; receptor-mediated endocytosis^[46]; receptor endocytosis and recycling^[21,47-50]; angiogenesis^[47]; regulation of the Wnt signaling pathway^[59]; coated vesicle cycle^[128]; regulation of protein subcellular localization^[129-130]; apoptosis^[8,51-52]; clathrin-coated pit (CCP) formation and cargo sorting^[131]; caspase-11-dependent pyroptosis^[53-54]; macroautophagy/autophagy^[9,34-35]	AD^[4]; impairment of learning and memory^[130]; vascular dementia^[129]; colon adenocarcinoma^[8]; breast cancer^[9]; bladder urothelial carcinoma^[10]; gastric cancer^[11]
	Numb	T102	Regulation of the Notch signaling pathway^[132]; coated pit maturation^[44]	-
	Eps15	-	Coated pit maturation^[44]	-
	IκBα	S536, K310	Regulation of the NF-κB signaling pathway^[53]	Ischemic stroke^[133]; pulmonary inflammatory^[53]
	Notch 1	-	Regulation of the Notch signaling pathway^[57]; promoted neural stem cell differentiation^[58]	Ischemic stroke^[58]
	REPS1/2, RALBP1	-	Epithelial-mesenchymal plasticity^[12]; increased therapy resistance^[12]	Hepatocellular carcinoma^[12]
GAK	Hsc70	-	Coated pit maturation^[134]	-
	Cyclin G	-	Regulation of cell-cycle^[74]	-
	TAp63	T46, T281	Tumorigenesis^[92]	-
	N-AChE-S	-	Apoptosis^[5]	AD^[5]
	IL12β a2	-	Cell signaling^[85]	-
	AR	-	Cell signaling^[13]	Prostate cancer^[13]
	Vha44	S543	Lysosomal acidification^[7]	PD^[6-7]
	AP2M1	T156	Regulation of CME^[135]; cell growth and centrosome duplication^[136]; endosomal pathway^[78]	-
	AP1	-	Receptor-mediated endocytosis^[82]; golgi to lysosome transport^[78,80]	-
	Atp1a3	T705	Resting membrane potential^[84]	PD^[84]
	Sipa1L1	T249	Brain developmental regulation^[84]	-
	CHC	T606	Regulation of mitosis^[89,137]	-
	PP2A	T104	Microtubule generation and outgrowth^[91]	-
	LRRK2	-	Regulation of neuron projection development^[138]	PD^[138]
BMP2K	AP2M1	T156	Regulation of CME^[98]	-
	CLINT1	T294	Sorting in TGN-endosome pathway^[31]	-
	ACKR3	-	Regulation of the GPCR signaling pathway^[102]	-
	CDK2	-	Polyploidization^[112]; regulation of bone mineralization^[107]	Osteoporosis^[107]; megakaryoblastic leukemia^[112]
STK16	DRG1	T100	Cellular growth^[119]	-
	STAT3	S727	Drug resistance^[14]	Triple-negative breast cancer^[14]
	c-MYC	S452	Ubiquitin-proteasome pathway^[15]	Colorectal cancer^[15]
	WDR1	-	Hepatic secretion^[122]	-
	AKT1	-	Regulation of AKT1 pathway^[16]; cell proliferation and apoptosis^[16]	Lung adenocarcinoma^[16]
	CNP/VEGF	-	Regulation of the TGF-β signaling pathway^[139]	-
	ELK1	-	Cell signaling^[123]	Brain lower grade glioma^[123]

NAKs members

Substrate proteins

Modification sites

Physiological functions

Related diseases

AAK1

AP2M1

T156

Regulation of CME^[45];

endosomal pathway^[46];

receptor-mediated endocytosis^[46];

receptor endocytosis and recycling^[21,47-50];

angiogenesis^[47];

regulation of the Wnt signaling pathway^[59];

coated vesicle cycle^[128];

regulation of protein subcellular localization^[129-130];

apoptosis^[8,51-52];

clathrin-coated pit (CCP) formation and cargo sorting^[131];

caspase-11-dependent pyroptosis^[53-54];

macroautophagy/autophagy^[9,34-35]

AD^[4];

impairment of learning and memory^[130];

vascular dementia^[129];

colon adenocarcinoma^[8];

breast cancer^[9];

bladder urothelial carcinoma^[10];

gastric cancer^[11]

Numb

T102

Regulation of the Notch signaling pathway^[132];

coated pit maturation^[44]

Eps15

Coated pit maturation^[44]

IκBα

S536, K310

Regulation of the NF-κB signaling pathway^[53]

Ischemic stroke^[133];

pulmonary inflammatory^[53]

Notch 1

Regulation of the Notch signaling pathway^[57];

promoted neural stem cell differentiation^[58]

Ischemic stroke^[58]

REPS1/2, RALBP1

Epithelial-mesenchymal plasticity^[12];

increased therapy resistance^[12]

Hepatocellular carcinoma^[12]

GAK

Hsc70

Coated pit maturation^[134]

Cyclin G

Regulation of cell-cycle^[74]

TAp63

T46, T281

Tumorigenesis^[92]

N-AChE-S

Apoptosis^[5]

AD^[5]

IL12β a2

Cell signaling^[85]

Cell signaling^[13]

Prostate cancer^[13]

Vha44

S543

Lysosomal acidification^[7]

PD^[6-7]

AP2M1

T156

Regulation of CME^[135];

cell growth and centrosome duplication^[136];

endosomal pathway^[78]

AP1

Receptor-mediated endocytosis^[82];

golgi to lysosome transport^[78,80]

Atp1a3

T705

Resting membrane potential^[84]

PD^[84]

Sipa1L1

T249

Brain developmental regulation^[84]

CHC

T606

Regulation of mitosis^[89,137]

PP2A

T104

Microtubule generation and outgrowth^[91]

LRRK2

Regulation of neuron projection development^[138]

PD^[138]

BMP2K

AP2M1

T156

Regulation of CME^[98]

CLINT1

T294

Sorting in TGN-endosome pathway^[31]

ACKR3

Regulation of the GPCR signaling pathway^[102]

CDK2

Polyploidization^[112];

regulation of bone mineralization^[107]

Osteoporosis^[107];

megakaryoblastic leukemia^[112]

STK16

DRG1

T100

Cellular growth^[119]

STAT3

S727

Drug resistance^[14]

Triple-negative breast cancer^[14]

c-MYC

S452

Ubiquitin-proteasome pathway^[15]

Colorectal cancer^[15]

WDR1

Hepatic secretion^[122]

AKT1

Regulation of AKT1 pathway^[16];

cell proliferation and apoptosis^[16]

Lung adenocarcinoma^[16]

CNP/VEGF

Regulation of the TGF-β signaling pathway^[139]

ELK1

Cell signaling^[123]

Brain lower grade glioma^[123]

NAKs members	Viruses	Substrate proteins of NAKs	Stage(s) of the viral life cycle involved	Inhibitors	References
AAK1	HPV	-	Immune evasion	-	[143]
HCV	AP2M1, AP1-A	Entry, assembly, release	Sunitinib	[18-21]
EGFR, Numb, AP2M1	Entry	Sunitinib	[21]
DENV	AP2M1, AP1M1	Entry, release	Sunitinib, Erlotinib	[19,23-25]
EBOV	AP2M1, AP1M1	Entry, release	Sunitinib, Erlotinib	[19,24]
RABV	AP2M1	Entry	Sunitinib	[32-33]
RSV	AP2M1	Immune evasion	-	[56]
SARS-CoV-2	AP2M1	Entry	Baricitinib, 1,2,4a,5-tetrahydro-4H-benzo[b] [1,4]oxazino[4,3-d] [1,4]oxazine scaffold and its derivatives, novel compounds (compounds 12, 11f, and nCorv-EMBS), SGC-AAK1-1-based inhibitors	[36-41,144]
NDV	AP1M1, AP2M1	Assembly/release	Sunitinib, Erlotinib	[145]
TOSV	AP2M1	Entry	Sunitinib	[146]
IAV	AP2M1	Immune evasion	-	[34-35]
LCMV	AP2M1	Immune evasion	-	[34]
PRV	Numb, Notch2	Activation	-	[132]
GAK	HCV	AP2M1, AP1-A	Entry, assembly, release	Sunitinib, isothiazolo[5,4-b]pyridine-based inhibitors	[18,20-22]
DENV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[26-29]
EBOV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[19,26]
CHIKV	-	-	Isothiazolo[4,3-b]pyridine-based inhibitors	[26]
SARS-CoV-2	AP2M1	Entry	RMC-242, Gefitinib, Baricitinib	[36,41]
NDV	AP1M1, AP2M1	Assembly, release	Sunitinib, Erlotinib	[145]
TOSV	AP2M1	Entry	Erlotinib	[146]
BMP2K	DENV	AP2M1, CLINT1	Entry, assembly/release	25A,5Z-7-oxozeaenol	[30-31]
HIV-1	-	Replication	-	[147]
SARS-CoV-2	-	Entry, assembly/release	Sunitinib, Erlotinib, RMC-76	[36]
VEEV	-	-	5Z-7-oxozeaenol	[30]
STK16	SARS-CoV-2	-	Entry, assembly/release	STK16-IN-1	[36]

NAKs

members

Viruses

Substrate proteins of NAKs

Stage(s) of the viral life cycle involved

Inhibitors

References

AAK1

HPV

Immune evasion

[143]

HCV