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Development Leptin signaling via JAK/STAT and MAPK cascades

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Development Leptin signaling via JAK/STAT and MAPK cascades

Leptin signaling via JAK/STAT and MAPK cascades

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

Six splice variants of the Leptin receptor have been identified: four shortisoforms (ObRa, ObRc, ObRd and ObRf) with shortened intra-cellular tails, the secretedisoform (ObRe) and the long isoform or ObRb. The long isoform consists of 1162 aminoacids and is the only Leptin receptor isoform with clearly demonstrated signalingcapability [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 STATproteins. Leptin signaling also results in Signal transducer and activator oftranscription 3 ( STAT3 ) binding, although STAT1, STAT5 and STAT6 may beactivated 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 dissociationfrom the receptor and dimerization. STAT3 dimers then translocate into the nucleusand act as transcription factors by binding to specific response elements in the promoterof 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 e xactmechanism Leptin -induced expression of CRP is unknown. It was shownhepatic 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 beidentified was the participation of the hormone in angiogenesis. One of key gene involvedin angiogenesis is Vascular endothelial growth factor A ( VEGF-A ) andLeptin induces upregulation of VEGF-A mRNA expression. This effect wasthought to be mediated in part, through the activation of STAT3 [8].P resumably Hypoxia-inducible factor 1, alpha subunit ( HIF1A ) may be involved inthis 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 inhibitorof 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 oncogenehomolog ( c-Fos ) and Early growth response 1 ( EGR1 ) and cellproliferation [10], [2]. Leptin stimulates the MAPKpathway in two different ways. One path is Leptin receptor binds Protein tyrosinephosphatase, non-receptor type 11 ( SHP-2 ) and together with its adapter moleculeGrowth factor receptor-bound protein 2 ( Grb2 ) activates downstream signalingeffects. In another way Jak2 associates with the Grb-2 and SHP-2 andthis complex activates further signaling steps [1]. In response toLeptin stimulation, c-Fos and EGR-1 stimulate production of severalgenes 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 toCytochrome c release and Caspases 3 and 9, apoptosis-related cysteine peptidases (Caspase-3, Caspase-9 ) activation, which coordinate the execution of thecell [12].

SHP-2 does not directly affect the STAT pathway. SHP-2 recognizes Tyr985of the L eptin receptor. SOCS-3 also recognizes and binds Tyr985 to exertits inhibitory effect. Therefore, SHP-2 and SOCS-3 are competitors andSHP-2 acts as an indirect positive regulator for STAT signaling [13].