STAT protein

From Wikipedia, the free encyclopedia

The Signal Transducers and Activator of Transcription (STAT) protein regulates many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced survival of tumors. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.

[edit] STAT family

The seven mammalian STAT family members identified are: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. STAT1 homodimers are involved in type II interferon signalling, and binds to the GAS (Interferon-Gamma Activated Sequence) promoter to induce expression of ISG (Interferon Stimulated Genes). In type I interferon signalling, STAT1-STAT2 heterodimer combines with IRF9 (Interferon Response Factor) to form ISGF3 (Interferon Stimulated Gene Factor), which binds to the ISRE (Interferon Stimulated Response Element) promoter to induce ISG expression.

[edit] STAT3

STAT3 is tyrosine-phosphorylated and activated by a number of kinases. The binding of IL-6 family cytokines (including IL-6, oncostatin M and leukemia inhibitory factor) to the gp130 receptor triggers STAT3 phosphorylation by JAK2. EGF-R and certain other receptor tyrosine kinases, such as c-MET phosphorylate STAT3 in response to their ligands.<ref>Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB and Chin YE (2004) "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells" in Mol Cell Biol Volume 24 (21), pages 9390-9400. Entrez PubMed 15485908 </ref> STAT3 is also a target of the c-src non-receptor tyrosine kinase.<ref>Silva CM (2004) "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis" in Oncogene Volume 23 (48), pages 8017-8023. Entrez PubMed 15489919 </ref>

STAT3-deficient mouse embryos can not develop beyond embryonic day 7 (E7.0), when gastrulation initiates.<ref>Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T and Akira S (1997) "Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality" in PNAS Volume 94 (8), pages 3801-3084. Entrez PubMed 9108058 </ref> It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells (ESCs). Indeed, LIF, which is supplied to ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means.<ref>Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T and Yokota T (1999) "STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells" in EMBO J Volume 18 (15), pages 4261-4269. Entrez PubMed 10428964 </ref>

Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.<ref name="Klampfer">Klampfer L (2006) "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs" in Curr Cancer Drug Targets Volume 6 (2), pages 107-121. Entrez PubMed 16529541 </ref><ref>Alvarez JV, Greulich H, Sellers WR, Meyerson M and Frank DA (2006) "Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor" in Cancer Res Volume 66 (6), pages 3162-3168. Entrez PubMed 16540667 </ref><ref>Yin W, Cheepala S, Roberts JN, Syson-Chan K, Digiovanni J and Clifford JL (2006) "Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions" in Mol Cancer Volume 5 (1), article number 15. Entrez PubMed 16603078 </ref><ref>Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T and Sekine I (2006) "Activation of STAT3 is a marker of poor prognosis in human colorectal cancer" in Oncol Rep Volume 15 (6), pages 1445-1451. Entrez PubMed 16685378 </ref> It has anti-apoptotic as well as proliferative effects.<ref name="Klampfer" />

[edit] Function

STAT proteins were originally described as latent cytoplasmic transcription factors that require phosphorylation for nuclear retention. The unphosphorylated STAT proteins shuttles between cytosol and the nucleus waiting for its activation signal. Once the activated transcription factors reaches the nucleus it binds to consensus DNA-recognition motif called gamma activated sites (GAS) in the promoter region of cytokine inducible genes and activates transcription of these genes.

[edit] Activation

Extracellular binding of cytokines induces activation of the intracellular Janus kinase that phosphorylates a specific tyrosine residue in the STAT protein which promotes the dimerization of STAT monomers via their SH2 domain. The phosphorylated dimer is then actively transported in the nucleus via importin a/b and RanGDP complex. Once inside the nucleus the active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site (GAS) motif and activate transcription of these genes. The STAT protein can be dephosphorylated by nuclear phosphatasess which leads to inactivation of STAT and the transcription factor becomes transported out of the nucleus by exportin crm1/RanGTP.

[edit] See also

• JAK-STAT pathway
• DNA-binding protein

[edit] References