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Gene interactions and pathways from curated databases and text-mining
Curr Mol Med 2003, PMID: 12776987

The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation.

Annerén, Cecilia; Lindholm, Cecilia K; Kriz, Vitezslav; Welsh, Michael

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.

Document information provided by NCBI PubMed

Text Mining Data

FRK/RAK-SHB → insulin receptor substrates (IRS): " The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 "

FRK/RAK-SHB → (IRS) -1: " The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 "

FRK/RAK-SHB → (IRS) -1 and -2: " The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 "

FRK/RAK-SHB → insulin receptor substrates (IRS): " The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 "

FRK/RAK-SHB → (IRS) -1: " The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 "

FRK/RAK-SHB → (IRS) -1 and -2: " The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 "

IL-2 → SHB: " In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production "

Manually curated Databases

  • OpenBEL Selventa BEL large corpus: Complex of PTK2-SHB → SRC (directlyIncreases, PTK2/SHB Activity)
    Evidence: Full text: SHB causes FAK activation in endothelial cells [17]. SHB binds FAK via its PTB domain in a phosphotyrosine-dependent manner, but the SHB PTB-domain binding site on FAK could not be identified. As a consequence of the FAK-SHB interaction, FAK becomes activated under conditions that promote endothelial cell differentiation. Furthermore, SRC is identified as a kinase that causes SHB and FAK phosphorylation.
  • OpenBEL Selventa BEL large corpus: PTK2 → SRC (directlyIncreases, PTK2 Activity)
    Evidence: Full text: SHB causes FAK activation in endothelial cells [17]. SHB binds FAK via its PTB domain in a phosphotyrosine-dependent manner, but the SHB PTB-domain binding site on FAK could not be identified. As a consequence of the FAK-SHB interaction, FAK becomes activated under conditions that promote endothelial cell differentiation. Furthermore, SRC is identified as a kinase that causes SHB and FAK phosphorylation.
  • OpenBEL Selventa BEL large corpus: SHB (increases)
    Evidence: Full text: The SHB mRNA contents were found to be regulated by both serine/threonine and tyrosine kinases, since genistein, a tyrosine kinase inhibitor, increased the SHB mRNA levels, as did okadaic acid, an inhibitor of serine/threonine phosphatases.
  • OpenBEL Selventa BEL large corpus: SHB (increases)
    Evidence: Full text: PDGF, FGF-2, NGF, CD3-stimulation (T cell receptor ligation), endostatin and Interleukin-2 all cause tyrosine phosphorylation of SHB if added to the appropriate target cells [12, 14, 16, 18-20].
  • OpenBEL Selventa BEL large corpus: SHD → ABL1 (directlyIncreases, SHD Activity)
    Evidence: Full text: ABL was found to associate with and phosphorylate the SHB homologue SHD [5].
  • OpenBEL Selventa BEL large corpus: Complex of PTPN11-SHB → FGF2 (increases)
    Evidence: Full text: SHB binds the activated FGFR-1 at tyrosine 766, which causes SRC-dependent tyrosine phosphorylation of SHB. SHB also associates constitutively to SHP-2, and upon FGF-2 stimulation, SHB/SHP-2 bridging promotes FRS-2 phosphorylation and activation. Thus, SHB is required for an adequate activation of the RAS/ERK pathway and endothelial cell cell mitogenesis [13].
  • OpenBEL Selventa BEL large corpus: SHB → FGFR1 (directlyIncreases, SHB Activity)
    Evidence: Full text: The PDGF receptors and FGFR-1 bind and cause tyrosine phosphorylation of SHB [12, 13].
  • OpenBEL Selventa BEL large corpus: SHB → IL2 (increases)
    Evidence: Full text: PDGF, FGF-2, NGF, CD3-stimulation (T cell receptor ligation), endostatin and Interleukin-2 all cause tyrosine phosphorylation of SHB if added to the appropriate target cells [12, 14, 16, 18-20].