Development - Growth hormone signaling via STATs and PLC/IP3

Growth hormone signaling via STATs and PLC/IP3

Growth hormone (GH or Somatotropin) is a major growth-promoting and metabolic regulatory hormone. Interaction of GH with its cell surface receptor (GHR) causes receptor dimerization and activation of the GHR-associated cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2) [1], [2], [3].

The signal transducers and activators of transcription (STATs) family of transcription factors are key molecules in the GH signaling process. GH-activated JAK2 phosphorylates at least four members of this family (STAT1, STAT3, STAT5A and STAT5B), leading to their dimerization, nuclear localization, DNA binding and activation of transcription [4]. STAT5A and STAT5B are the predominant STATs utilized by GH [5].

GH stimulates activation of at least two tyrosine kinases, v-Src sarcoma viral oncogene homolog (c-Src) and FYN oncogene related to SRC, FGR, YES (Fyn) [6], both of which exist as components of a multiprotein signaling complex centered on an adapter protein v-Crk sarcoma virus CT10 oncogene homolog (Crk) and Crk-associated substrate Breast cancer anti-estrogen resistance 1 (p130Cas).

GH also activates PTK2 protein tyrosine kinase 2 (FAK1) via its phosphorylation by JAK2. This activation results in tyrosine phosphorylation of the two FAK1-associated substrates, namely, Paxillin and Tensin [7]. GH stimulates the reorganization of the actin cytoskeleton in cells with fibroblastic morphology [8].

Moreover GH signaling can activate Mitogen-activated protein kinase 8 (JNK1) via formation of multiprotein complex encompassing FAK1-associated Crk and Rap guanine nucleotide exchange factor 1 (C3G) [9]. Crk directly binds and activates JNK1 [10]. JNK1 then phosphorylates Jun oncogene (c-Jun) and activates its transcriptional activity [11].

GH also activates RAS-related protein-1 (Rap1) via Crk-p130Cas assembly. Rap1 controls cell invasion and survival [9].

GH exerts many of its physiological functions by regulating the transcription of genes for a variety of proteins, including Insulin-like growth factor-1 (IGF-1), Fibrinogen beta and transcription factors such as Interferon regulatory factor 1 (IRF1) and v-Fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos). These target genes are regulated via STAT transcription factors [12], [13], [14], [15], [16].

Phospholipase C gamma (PLC-gamma) is tyrosine phosphorylated via its direct binding to the JAK2/GHR complexes. PLC-gamma catalyzes the production of the second messenger metabolites, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), leading to intracellular Ca(II) mobilization and protein kinase C activation (such as PKC-delta) [17], [18], [19].

Moreover it has been recently found that PLC-gamma 1 is also involved in negative regulation of GHR signaling via direct binding to JAK2. This binding lead to the activation of PLC-gamma 1 and, via a feedback mechanism, PLC-gamma 1 can inhibit JAK2 activity by recruiting Protein tyrosine phosphatase, non-receptor type 1 (PTP-1B) [20].

The mechanisms by which GH signaling can be attenuated also employ suppressors of cytokine signaling (SOCS) protein family such as SOCS1, SOCS2 and SOCS3. The latter proteins play important roles in regulating GH-regulated processes [21]. The transmembrane metalloproteinase ADAM17 can cleave and inactivate GHR [22].

References:

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