Pathway Map Details

Development_Leptin signaling via JAK/STAT and MAPK cascades



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STAT3, HIF1A, cPLA2, VEGF-A, H-RAS, JAK2, PIAS3, CRP, MEK1(MAP2K1), TIMP1, SHP-2, POMC, GRB2, c-Raf-1, Cytochrome c, Endothelin-1, SOS, c-Fos, Leptin receptor, Leptin, Thyroliberin, SOCS3, Erk (MAPK1/3), EGR1, STAT3, PTP-1B

Description:

Leptin signaling via JAK/STAT and MAPK cascades

Leptin, the polypeptide product of the ob gene, acts on the brain to regulate energy balance. It is hormone, composed of 167 amino acid residues and produced almost exclusively in adipose tissue. More-recent studies have revealed additional pleiotrophic functions of Leptin, including the ability to affect neuroendocrine functions, the adaptive response to fasting, reproductive function, brain size, bone development, immune function, blood cell development, regulation of blood pressure, glucose homeostasis, fatty acid metabolism, and regulation of sensory nerve input and autonomic outflow [1].

Six splice variants of the Leptin receptor have been identified: four short isoforms (ObRa, ObRc, ObRd and ObRf) with shortened intra-cellular tails, the secreted isoform (ObRe) and the long isoform or ObRb. The long isoform consists of 1162 amino acids and is the only Leptin receptor isoform with clearly demonstrated signaling capability [1].

Leptin signaling occurs typically through the JAK/STAT pathway. Janus kinase 2 ( JAK2 ) activation leads to tyrosine phosphorylation of Leptin receptor. Phosphorylated Tyr1138 of Leptin receptor serves as a binding site for STAT proteins. Leptin signaling also results in Signal transducer and activator of transcription 3 ( STAT3 ) binding, although STAT1, STAT5 and STAT6 may be activated by Leptin as well [1], [2], [3].

After STAT3 recruitment (and other STATs) to Leptin receptor, STAT3 becomes tyrosine-phosphorylated by JAK2, which leads to dissociation from the receptor and dimerization. STAT3 dimers then translocate into the nucleus and act as transcription factors by binding to specific response elements in the promoter of their target genes, such as Suppressor of cytokine signaling 3 ( SOCS-3 ), Proopiomelanocortin ( POMC ) [4], Thyroliberin [5], TIMP metallopeptidase inhibitor 1 ( TIMP1 ) [6], C-reactive protein, pentraxin-related ( CRP ) [7]. The exact mechanism Leptin -induced expression of CRP is unknown. It was shown hepatic production of CRP is a Phosphoinositide-3-kinase (PI3K)-dependent process. CRP is known to directly inhibit the binding of Leptin to its receptors, blocking signal transmission. [7].

Among the many extraneuronal effects of Leptin, one of the first to be identified was the participation of the hormone in angiogenesis. One of key gene involved in angiogenesis is Vascular endothelial growth factor A ( VEGF-A ) and Leptin induces upregulation of VEGF-A mRNA expression. This effect was thought to be mediated in part, through the activation of STAT3 [8]. Presumably Hypoxia-inducible factor 1, alpha subunit ( HIF1A ) may be involved in this pathway [3].

Leptin -induced JAK/STAT signaling pathway can be inhibited by SOCS-3, Protein tyrosine phosphatase, non-receptor type 1 ( PTP-1B ) and Protein inhibitor of activated STAT, 3 ( PIAS3 ) [9], [1], [3].

Leptin also activates the Mitogen-activated protein kinase 1-3 ( ERK1/2 ) pathway leading to the induction of v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) and Early growth response 1 ( EGR1 ) and cell proliferation [10], [2]. Leptin stimulates the MAPK pathway in two different ways. One path is Leptin receptor binds Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 ) and together with its adapter molecule Growth factor receptor-bound protein 2 ( Grb2 ) activates downstream signaling effects. In another way Jak2 associates with the Grb-2 and SHP-2 and this complex activates further signaling steps [1]. In response to Leptin stimulation, c-Fos and EGR-1 stimulate production of several genes including TIMP-1 [6], and Endothelin-1 [11] [3].

Leptin can also induce apoptosis via RAS-ERK cascade. In this case, Erk1/2 activates Cytosolic phospholipase A2 ( cPLA2 ) that leads to Cytochrome c release and Caspases 3 and 9, apoptosis-related cysteine peptidases ( Caspase-3, Caspase-9 ) activation, which coordinate the execution of the cell [12].

SHP-2 does not directly affect the STAT pathway. SHP-2 recognizes Tyr985 of the L eptin receptor. SOCS-3 also recognizes and binds Tyr985 to exert its inhibitory effect. Therefore, SHP-2 and SOCS-3 are competitors and SHP-2 acts as an indirect positive regulator for STAT signaling [13].

References:

  1. Hegyi K, Fulop K, Kovacs K, Toth S, Falus A
    Leptin-induced signal transduction pathways. Cell biology international 2004;28(3):159-69
  2. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, Vizzutti F, Anania FA, Milani S, Rombouts K, Laffi G, Pinzani M, Marra F
    Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology (Baltimore, Md.) 2005 Dec;42(6):1339-48
  3. Fruhbeck G
    Intracellular signalling pathways activated by leptin. The Biochemical journal 2006 Jan 1;393(Pt 1):7-20
  4. Munzberg H, Huo L, Nillni EA, Hollenberg AN, Bjorbaek C
    Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 2003 May;144(5):2121-31
  5. Huo L, Munzberg H, Nillni EA, Bjorbaek C
    Role of signal transducer and activator of transcription 3 in regulation of hypothalamic trh gene expression by leptin. Endocrinology 2004 May;145(5):2516-23
  6. Cao Q, Mak KM, Ren C, Lieber CS
    Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways. The Journal of biological chemistry 2004 Feb 6;279(6):4292-304
  7. Chen K, Li F, Li J, Cai H, Strom S, Bisello A, Kelley DE, Friedman-Einat M, Skibinski GA, McCrory MA, Szalai AJ, Zhao AZ
    Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nature medicine 2006 Apr;12(4):425-32
  8. Suganami E, Takagi H, Ohashi H, Suzuma K, Suzuma I, Oh H, Watanabe D, Ojima T, Suganami T, Fujio Y, Nakao K, Ogawa Y, Yoshimura N
    Leptin stimulates ischemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes 2004 Sep;53(9):2443-8
  9. Lothgren A, McCartney M, Rupp Thuresson E, James SR
    A model of activation of the protein tyrosine phosphatase SHP-2 by the human leptin receptor. Biochimica et biophysica acta 2001 Feb 9;1545(1-2):20-9
  10. Banks AS, Davis SM, Bates SH, Myers MG Jr
    Activation of downstream signals by the long form of the leptin receptor. The Journal of biological chemistry 2000 May 12;275(19):14563-72
  11. Quehenberger P, Exner M, Sunder-Plassmann R, Ruzicka K, Bieglmayer C, Endler G, Muellner C, Speiser W, Wagner O
    Leptin induces endothelin-1 in endothelial cells in vitro. Circulation research 2002 Apr 5;90(6):711-8
  12. Kim GS, Hong JS, Kim SW, Koh JM, An CS, Choi JY, Cheng SL
    Leptin induces apoptosis via ERK/cPLA2/cytochrome c pathway in human bone marrow stromal cells. The Journal of biological chemistry 2003 Jun 13;278(24):21920-9
  13. Bjorbaek C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, Gu H, Neel BG, Myers MG Jr, Flier JS
    Divergent roles of SHP-2 in ERK activation by leptin receptors. The Journal of biological chemistry 2001 Feb 16;276(7):4747-55