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Development Growth hormone signaling via PI3K/AKT and MAPK cascades


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Development Growth hormone signaling via PI3K/AKT and MAPK cascades

Growth hormone signaling via PI3K and MAPK cascades

Growth hormone (GH or Somatotropin ) is a major growth-promoting and metabolicregulatory hormone. Interaction of Somatotropin with Growth hormone receptor (GHR ), by virtue of receptor dimerization, causes activation of GHR associatedcytoplasmic tyrosine kinase, Janus kinase 2 ( JAK2 ) [1].Almost alldownstream signaling pathways utilized by Somatotropin require JAK2activity [2], [3].

Somatotropin effects include stimulation of amino acid transport, proteinsynthesis, glucose transport, lipogenesis, gene expression, mitogenesis, prevention ofapoptosis, differentiation and reorganization of cytoskeletal architecture [4].

Somatotropin activates Mitogen activated protein kinase 1 ( ERK2 )[5], [6] and Mitogen activated protein kinase 14 ( p38alpha(MAPK14) ) [7] via JAK2 -associated adapter proteins Src homology2 domain containing transforming protein 1 ( Shc ) and Growth factorreceptor-bound protein 2 ( Grb2 ) [8]. Somatotropin stimulationresults in the assembly of a Shc - GRB2 - Son of sevenless homologes (SOS ) complex with the resultant activation of v-Ha-ras Harvey rat sarcoma viraloncogene homolog ( H-RAS ) and subsequent engagement of the -raf-1 murine leukemiaviral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 (MEK1(MAP2K1)/ ERK2 pathway [9]. In response toSomatotropin signaling, ERK2 phosphorylates and activates severaltranscription factors including Activating transcription factor 2 ( ATF-2 ), ELK1,member of ETS oncogene family ( Elk-1 ) and ELK4, ETS-domain protein ()Elk-4. Ternary complex factors Elk-1 and Elk-4 mediateSomatotropin -induced transcription of Early growth response factor-1 (EGR1 ), v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) andJun B proto-oncogene ( JunB ) genes [10], [11].

Activation of p38alpha (MAPK14) by Somatotropin is the JAK2-dependent process involving PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) )and Mitogen-activated protein kinase kinase kinase 4 ( MEKK4(MAP3K4) )/Mitogen-activated protein kinase kinase 3 ( MEK3(MAP2K3) ) activation [12]. p38alpha (MAPK14) is required for Somatotropin -inducedATF-2, DNA-damage-inducible transcript 3 ( C/EBP zeta ) and CCAAT/enhancerbinding protein (C/EBP), beta ( C/EBPbeta ) transcription activity, reorganizationof the actin cytoskeleton and mitogenesis [7].

A critical transcription factor of Somatotropin action is the transcriptionactivator C/EBPbeta that is necessary for transcription of v-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ) gene [13]. Regulation ofC/EBPbeta activity is mediated both by p38alpha (MAPK14) andPhosphatidylinositol 3-kinase ( PI3K )/ V-akt murine thymoma viral oncogenehomolog 1 ( AKT(PKB) ) pathways.

Somatotropin -dependent tyrosyl phosphorylation of adaptor proteins Insulinreceptor substrates 1 and 2 ( IRS-1, IRS-2 ) by JAK2 leads to theincreased association of IRS-1 with Shc/ GRB2 complex, and theassociation of IRS-1 and IRS-2 with the Phosphoinositide-3-kinase,regulatory subunit 1 ( PI3K reg class IA (p85 alpha) ) and Protein tyrosinephosphatase, non-receptor type 11 ( SHP-2 ) [14]. PI3K reg class IA(p85-alpha) can bind directly to the phosphorylated tyrosine residues at thecarboxyl-terminal part of the Somatotropin receptor, providing a directalternative route for the activation of Phosphoinositide-3-kinase, catalytic, alphapolypeptide ( PI3K cat class IA (p110-alpha) ) [15].

Somatotropin activates serine/threonine kinase AKT(PKB) in a PI3K-dependent manner [16]. AKT(PKB) inhibits Glycogen synthase kinase 3beta ( GSK3 beta ) and attenuates its negative control of C/EBPbetaactivity. PI3K/ AKT(PKB)/ GSK3 beta pathway mediates signalingbetween Somatotropin receptor and the nucleus, promoting activation ofC/EBPbeta [17].

Somatotropin also initiates PI3K/ GSK3 beta signaling to deliveran antiapoptotic signal [16].

Somatotropin -stimulated Ribosomal protein S6 kinase, 70kDa, polypeptide 1 (p70 S6 kinase 1 ) activation is probably mediated through a PI3K/AKT(PKB) pathway including Tuberous sclerosis 2 ( Tuberin )/ Ras homologenriched in brain ( RHEB2 )/ FK506 binding protein 12-rapamycin associated protein1 ( mTOR ) pathway [18]

Cytokine receptor signal transduction is controlled by limitation of the magnitude andduration of the signal through negative regulation. The mechanisms by whichSomatotropin signaling can be attenuated include tyrosine dephosphorylation ofJAK2 and IRS-1 by phosphatases Protein tyrosine phosphatase, non-receptortype 6 ( SHP-1 ) and SHP-2, and cleavage of GHR by ADAMmetallopeptidase domain 17 ( ADAM17 ) with subsequently GHR inactivation[14], [19], [20].