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 metabolic regulatory hormone. Interaction of Somatotropin with Growth hormone receptor (GHR), by virtue of receptor dimerization, causes activation of GHR associated cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2) [1].Almost all downstream signaling pathways utilized by Somatotropin require JAK2 activity [2], [3].

Somatotropin effects include stimulation of amino acid transport, protein synthesis, glucose transport, lipogenesis, gene expression, mitogenesis, prevention of apoptosis, 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 homology 2 domain containing transforming protein 1 (Shc) and Growth factor receptor-bound protein 2 (Grb2) [8]. Somatotropin stimulation results in the assembly of a Shc-GRB2- Son of sevenless homologes (SOS) complex with the resultant activation of v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS) and subsequent engagement of the -raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 (MEK1(MAP2K1)/ ERK2 pathway [9]. In response to Somatotropin signaling, ERK2 phosphorylates and activates several transcription 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 mediate Somatotropin -induced transcription of Early growth response factor-1 (EGR1), v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) and Jun 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 -induced ATF-2, DNA-damage-inducible transcript 3 (C/EBP zeta) and CCAAT/enhancer binding protein (C/EBP), beta (C/EBPbeta) transcription activity, reorganization of the actin cytoskeleton and mitogenesis [7].

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

Somatotropin -dependent tyrosyl phosphorylation of adaptor proteins Insulin receptor substrates 1 and 2 (IRS-1, IRS-2) by JAK2 leads to the increased association of IRS-1 with Shc/GRB2 complex, and the association of IRS-1 and IRS-2 with the Phosphoinositide-3-kinase, regulatory subunit 1 (PI3K reg class IA (p85 alpha)) and Protein tyrosine phosphatase, non-receptor type 11 (SHP-2) [14]. PI3K reg class IA (p85-alpha) can bind directly to the phosphorylated tyrosine residues at the carboxyl-terminal part of the Somatotropin receptor, providing a direct alternative route for the activation of Phosphoinositide-3-kinase, catalytic, alpha polypeptide (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 3 beta (GSK3 beta) and attenuates its negative control of C/EBPbeta activity. PI3K/ AKT(PKB)/ GSK3 beta pathway mediates signaling between Somatotropin receptor and the nucleus, promoting activation of C/EBPbeta [17].

Somatotropin also initiates PI3K/ GSK3 beta signaling to deliver an 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 homolog enriched in brain (RHEB2)/ FK506 binding protein 12-rapamycin associated protein 1 (mTOR) pathway [18]

Cytokine receptor signal transduction is controlled by limitation of the magnitude and duration of the signal through negative regulation. The mechanisms by which Somatotropin signaling can be attenuated include tyrosine dephosphorylation of JAK2 and IRS-1 by phosphatases Protein tyrosine phosphatase, non-receptor type 6 (SHP-1) and SHP-2, and cleavage of GHR by ADAM metallopeptidase domain 17 (ADAM17) with subsequently GHR inactivation [14], [19], [20].

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