Growth hormone signaling via STATs and
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) , , .
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
STAT5A and STAT5B), leading to
their dimerization, nuclear localization, DNA binding and activation of transcription
. STAT5A and
STAT5B are the predominant STATs utilized by GH .
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)
, 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
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 . GH stimulates the reorganization of the actin cytoskeleton in cells with
fibroblastic morphology .
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) .
Crk directly binds and activates
JNK1 . JNK1
then phosphorylates Jun oncogene (c-Jun) and activates its
transcriptional activity .
GH also activates RAS-related protein-1 (Rap1) via
Rap1 controls cell invasion and survival .
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 , , , , .
Phospholipase C gamma (PLC-gamma) is tyrosine
phosphorylated via its direct binding to the
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) , , .
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
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 . The
transmembrane metalloproteinase ADAM17 can cleave and
inactivate GHR .
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