The FRK / RAK-SHB Signaling Cascade: A Versatile Signal- Transduction Pathway that Regulates Cell Survival, Differentiation and Proliferation

Abstract

Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK). FRK/RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where they both induce PC12 cell differentiation and beta-cell proliferation. Furthermore, beta-cell apoptosis is augmented by these proteins under conditions that cause beta-cell degeneration. The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development. In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.

Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

“…The mechanistic explanations to the reduced signaling responses to VEGF in Shb knockout endothelial cells remain elusive. Shb is a multi-domain adapter protein that may interact with Src kinases, PLCγ, PI3kinase, FAK, Crk and ras-GAP [25], and consequently, perturbations in one or several of these signaling pathways may yield the presently observed results.…”

The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity

“…Notably, Shb has also been found to regulate the cell cycle in the pancreas and blood system in a cell type dependent manner. For example, overexpression of Shb promotes proliferation in endothelial cells and in neonatal pancreatic β-cells [20].…”

“…The Cterminal SH2-domain of Shb [20] facilitates interactions with receptor tyrosine kinases such as vascular endothelial growth factor receptor-2 (VEGFR-2) [21], platelet derived growth factor receptor (PDGFR) [22] and the T cell receptor (TCR) [18,23]. Moreover, Shb associates via its other domains with additional signaling elements such as SH2 domaincontaining leukocyte protein of 76 kDa (Slp76) [23], Vav1 [23], c-Abl [24], FAK [17], phospholipase C-γ (PLCγ), Src, and phosphatidylinositol-3 kinase (PI3K), acting as a scaffold in signaling cascades [20]. Several of Shb's known interaction partners, including PDGFR [25], TCR [26], Vav1 [27], and FAK [28], are established regulators of blood cell development and function.…”

Genome-wide discovery of Pax7 target genes during development

“…PCR primers and conditions are provided in Supplemental Table S1. 1 Densitometric quantification was used to measure product; 10 l of all reactions were resolved by 1.5% agarose gel electrophoresis and ethidium bromide staining, followed by fluorescence quantification using QuantityOne software (Bio-Rad). Fold enrichment was determined (expressed as ϩPax7-specific antibody/no antibody) and subjected to unpaired two-tailed t-tests using StatistiXL v1.…”