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JAK/STAT Signaling

JAK-STAT信号传导在脊椎动物甚至一些其他后生动物中均高度保守。受体激活蛋白激酶与转录因子的结合使该信号传导级联成为中央细胞调节通路之一。

脊椎动物中的JAK-STAT信号传导依赖于蛋白激酶和转录因子构成的网络,用以整合来自不受体系统的信号。众多的刺激包括细胞因子、生长因子和激素,与它们的结合最终影响了免疫应答调节和细胞生长、存活和分化等过程。

根据各成分的功能,高度保守通路基本涉及三个传入信息处理层次:

  • 配体与受体的结合引起受体分子的构象变化。
  • 受体这种空间变化使与受体或受体亚基结合的两个酪氨酸激酶(JAK)紧密接近,从而促使反式磷酸化。激活的酪氨酸激酶随后磷酸化其他靶点。
  • 主要的磷酸化靶点为信号转导及转录激活因子(STAT)。JAKs磷酸化前,这些转录因子在细胞质中处于非活性状态。一旦指向STAT C末端的保守酪氨酸被磷酸化,它便可以在与另一STAT SH2结构域的结合中充当二聚体界面。然后,这些激活的STAT二聚体被转运至细胞核并与特异DNA基序结合,从而激活靶基因的转录。

此外,在多个层面上均存在对这些过程的负调节。

  • 细胞因子信号转导抑制因子(SOCS)的基因转录受到激活的STATs的刺激。通过与磷酸化JAKs或受体结合,SOCS会使信号传导失活,或促进JAK泛素化。
  • 激活STATs的蛋白抑制剂(PIAS)会与激活STATs结合,从而阻止其与DNA结合。
  • 蛋白酪氨酸磷酸酶(PTP)可扭转JAKs的活性。

原型JAK-STAT信号转导通路具有明显的线性特征。然而,通过受体酪氨酸激酶(RTKs),与其他信号传导级联(如MAPK通路和JAK的独立STAT磷酸化)会发生较大串扰。

JAK

STAT

STAT1 (Signal Transducer and Activator of Transcription 1, 91kDa):

STAT2 (Signal Transducer and Activator of Transcription 2, 113kDa):

STAT3 (Signal Transducer and Activator of Transcription 3 (Acute-Phase Response Factor)):

STAT4 (Signal Transducer and Activator of Transcription 4):

STAT5A (Signal Transducer and Activator of Transcription 5A):

STAT5B (Signal Transducer and Activator of Transcription 5B):

STAT6 (Signal Transducer and Activator of Transcription 6, Interleukin-4 Induced):

SOCS

SOCS1 (Suppressor of Cytokine Signaling 1):

SOCS2 (Suppressor of Cytokine Signaling 2):

CISH (Cytokine Inducible SH2-Containing Protein):

SOCS3 (Suppressor of Cytokine Signaling 3):

SOCS4 (Suppressor of Cytokine Signaling 4):

SOCS5 (Suppressor of Cytokine Signaling 5):

SOCS6 (Suppressor of Cytokine Signaling 6):

PIAS

PIAS1 (Protein Inhibitor of Activated STAT, 1):

PIAS3 (Protein Inhibitor of Activated STAT, 3):

PIAS2 (Protein Inhibitor of Activated STAT, 2):

PIAS4 (Protein Inhibitor of Activated STAT, 4):

PTP

PTPN11 (Protein tyrosine Phosphatase, Non-Receptor Type 11):

FYN (FYN Oncogene Related To SRC, FGR, YES):

Src (Proto-oncogene tyrosine-protein kinase Src):

GP130 family

CNTF (Ciliary Neurotrophic Factor):

IL11RA (Interleukin 11 Receptor, alpha):

IL12RB1 (Interleukin 12 Receptor beta 1):

IL12RB2 (Interleukin 12 Receptor, beta 2):

IL6RA (Interleukin 6 Receptor, alpha):

LIF (Leukemia Inhibitory Factor):

LIFR (Leukemia Inhibitory Factor Receptor alpha):

Homodimeric receptors

betaC family

gammaC family

GPCR

GNAQ (Guanine Nucleotide Binding Protein (G Protein), Q Polypeptide):

HTR2A (5-Hydroxytryptamine (serotonin) Receptor 2A):

HTR7 (5-Hydroxytryptamine (serotonin) Receptor 7 (Adenylate Cyclase-Coupled)):

Ang II/III - Angiotensin II/III:

AGT (Angiotensinogen (serpin Peptidase Inhibitor, Clade A, Member 8)):

HTR1F (5-Hydroxytryptamine (serotonin) Receptor 1F):

Interferons

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