Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells

Manuvakhova, Marina; Thottassery, Jaideep V.; Hays, Susan; Qu, Zhican; Rentz, Sarah S.; Westbrook, Louise; Kern, Florian

doi:10.1038/sj.onc.1209592

Cited by 15 publications

(18 citation statements)

References 59 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Stimulation of different cell types with FGF-1 resulted in the formation of multiple complexes involving FRS2, GAB1, SOS1, PTPN11, SHC1, SH2B1, and GRB2 [53–60]. These complexes are critical to the subsequent activation of Ras [53, 56]. Association of Ras with Raf kinase [53] induces autophosphorylation and activation of Raf.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A Network Map of FGF-1/FGFR Signaling System

Raju

Palapetta

Sandhya

et al. 2014

Journal of Signal Transduction

View full text Add to dashboard Cite

Fibroblast growth factor-1 (FGF-1) is a well characterized growth factor among the 22 members of the FGF superfamily in humans. It binds to all the four known FGF receptors and regulates a plethora of functions including cell growth, proliferation, migration, differentiation, and survival in different cell types. FGF-1 is involved in the regulation of diverse physiological processes such as development, angiogenesis, wound healing, adipogenesis, and neurogenesis. Deregulation of FGF-1 signaling is not only implicated in tumorigenesis but also is associated with tumor invasion and metastasis. Given the biomedical significance of FGFs and the fact that individual FGFs have different roles in diverse physiological processes, the analysis of signaling pathways induced by the binding of specific FGFs to their cognate receptors demands more focused efforts. Currently, there are no resources in the public domain that facilitate the analysis of signaling pathways induced by individual FGFs in the FGF/FGFR signaling system. Towards this, we have developed a resource of signaling reactions triggered by FGF-1/FGFR system in various cell types/tissues. The pathway data and the reaction map are made available for download in different community standard data exchange formats through NetPath and NetSlim signaling pathway resources.

show abstract

Section: Resultsmentioning

confidence: 99%

“…These complexes are critical to the subsequent activation of Ras [53, 56]. Association of Ras with Raf kinase [53] induces autophosphorylation and activation of Raf. Activation of Raf leads to phosphorylation dependent activation of Map kinases 1/2 (MAP2K1/2) and subsequently Erk2/1 (MAPK1/3) [60–62].…”

Section: Resultsmentioning

confidence: 99%

A Network Map of FGF-1/FGFR Signaling System

Raju

Palapetta

Sandhya

et al. 2014

Journal of Signal Transduction

View full text Add to dashboard Cite

show abstract

“…Keloids also increase expression of fibroblast growth factor (FGF) during skin injury (53). More recently, the PI3-K/mTOR pathway was shown to be required in HIF-1a activity in Akt-induced tumor growth (57) and FGF-1 induced phosphorylation of p70S6K in human breast carcinoma cells (58). More recently, the PI3-K/mTOR pathway was shown to be required in HIF-1a activity in Akt-induced tumor growth (57) and FGF-1 induced phosphorylation of p70S6K in human breast carcinoma cells (58).…”

Section: Discussionmentioning

confidence: 99%

mTOR as a potential therapeutic target for treatment of keloids and excessive scars

Ong

Khoo

Mukhopadhyay

et al. 2007

Experimental Dermatology

View full text Add to dashboard Cite

Keloid is a dermal fibroproliferative disorder characterized by excessive deposition of extracellular matrix (ECM) components such as collagen, glycoproteins and fibronectin. The mammalian target of rapamycin (mTOR) is a serine/theronine kinase which plays an important role in the regulation of metabolic processes and translation rates. Published reports have shown mTOR as regulator of collagen expression and its inhibition induces a decrease in ECM deposition. Our aim was to investigate the role of mTOR in keloid pathogenesis and investigate the effect of rapamycin on proliferating cell nuclear antigen (PCNA), cyclin D1, collagen, fibronectin and alpha-smooth muscle actin (alpha-SMA) expression in normal fibroblasts (NF) and keloid fibroblasts (KF). Tissue extracts obtained from keloid scar demonstrated elevated expression of mTOR, p70KDa S6 kinase (p70S6K) and their activated forms, suggesting an activated state in keloid scars. Serum stimulation highlighted the heightened responsiveness of KF to mitogens and the importance of mTOR and p70S6K during early phase of wound healing. Application of rapamycin to monoculture NF and KF, dose- and time-dependently downregulates the expression of cytoplasmic PCNA, cyclin D1, fibronectin, collagen and alpha-SMA, demonstrating the anti-proliferative effect and therapeutic potential of rapamycin in the treatment of keloid scars. The inhibitory effect of rapamycin was found to be reversible following recovery in the expression of proteins following the removal of rapamycin from the culture media. These results demonstrate the important role of mTOR in the regulation of cell cycle and the expression of ECM proteins: fibronectin, collagen and alpha-SMA.

show abstract

“…Consistent with this idea, expression of the PTB domain of FRS2α inhibits antiestrogen growth of breast carcinoma cells induced by overexpression of FGF1. ( 59 )…”

Section: Relevance Of Frs2 Proteins To Cancermentioning

confidence: 99%

Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins

Gotoh¹

2008

Cancer Science

238

205

View full text Add to dashboard Cite

The FRS2 family of adaptor/scaffold proteins has two members, FRS2a and FRS2b. Both proteins contain N-terminal myristylation sites for localization on the plasma membrane and a PTB domain for binding to limited species of receptor tyrosine kinases (RTKs), including the FGF receptor, the neurotophin receptor, RET, and ALK. Activation of these RTKs allows FRS2 proteins to become phosphorylated of tyrosine residues and then bind to Grb2 and Shp2, a SH2 domain-containing adaptor and a tyrosine phosphatase, respectively. Subsequently, Shp2 activates a Ras/ERK pathway and Grb2 activates a Ras/ERK, phosphatidyl inositol (PI)-3 kinase and ubiquitination/ degradation pathways by binding to SOS, Gab1, and Cbl via the SH3 domains of Grb2. FRS2a acts as 'a conning center' in FGF signaling mainly because it induces sustained levels of activation of ERK via Shp2-binding sites and Grb2-binding sites, though the contribution of the former is greater. Ample amounts of evidence indicate that proteins lacking catalytic activity, so called scaffolding adaptor proteins, relay many key events of signal transduction from upstream components such as receptors to downstream elements.(1-3) The scaffold adaptor proteins that are upstream of RTK signal transduction are classified into two groups. One is comprised of docking proteins that have multiple tyrosine phosphorylation sites to dock downstream signaling proteins. They also often have other domains to bind other molecules. This group includes fibroblast growth factor (FGF) receptor substrate 2 (FRS2), a new SH2-containing sequence (Shc), Grb2-associated binder (Gab), (4,5) insulin receptor substrate (IRS), and downstream of kinase (Dok)-family proteins.(6) Several proteins in this group are subdivided into a group of membrane-linked docking proteins (MLDP) (7) (Fig. 1). MLDP is localized in the lipid component of plasma membranes, since the protein contains a membrane-anchor domain of a stretch of hydrophobic amino acid residues and/or a pleckstrin homology (PH) domain at or close to the N-terminus. The other is comprised of adaptor proteins in a narrow sense. They have only SH3 or/and SH2 domains to bind signaling proteins. (7,8) This group includes Grb2, Crk, and Nck.Some of the scaffold adaptor proteins have a phosphotyrosine binding (PTB) domain or a Src homology (SH)2 domain to bind specific residues containing a tyrosine residue that becomes phosphorylated by activated RTKs or other tyrosine kinases. All the scaffold adaptor proteins act in the specification and/or amplification of the signal transduction pathway. Since these scaffold proteins were first discovered almost two decades ago, signal transduction pathways have emerged as a very complex network. In this review, I would like to summarize what is known about FRS2 proteins, a relatively new family of docking/ adaptor proteins.FRS2 stands for FGF receptor substrate 2. (9) What then is FGF receptor substrate 1? It is actually PLCγ, which was identified as the first substrate of FGF receptor tyrosine kinases. (10) FRS2 is...

show abstract

Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells

Cited by 15 publications

References 59 publications

A Network Map of FGF-1/FGFR Signaling System

A Network Map of FGF-1/FGFR Signaling System

mTOR as a potential therapeutic target for treatment of keloids and excessive scars

Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins

Contact Info

Product

Resources

About