Critical role for the docking-protein FRS2α in FGF receptor-mediated signal transduction pathways

Hadari, Yaron R.; Gotoh, Noriko; Kouhara, Haruhiko; Lax, Irit; Schlessinger, Joseph

doi:10.1073/pnas.161259898

Cited by 264 publications

(281 citation statements)

References 24 publications

(28 reference statements)

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“…Although the same sequence was not detected in the aa 248-272 region, the most important components of this domainthe positively charged lysine residues and the hydrophobic leucine residues -were spread throughout the region. In combination with the results of our pull-down assays using the point-mutated FRS2, our data suggest that a putative novel ERK2-docking motif, namely, KX (1)(2) LX (2-6) K(X)L, is essential for the formation of the FRS2-ERK2 complex ( Figure 2B). …”

Section: Identification Of the Erk2-docking Site In Frs2supporting

confidence: 68%

“…First, loss of FRS3 FRS2 is not simply a link to the MAPK cascade but is a pivotal signal organizer. PY of FRS2 leads to Grb2-mediated complex formation with Gab1, resulting in the recruitment and activation of PI3-kinase [2,7]. VEGF treatment leads to the recruitment of Nck, p21-activated kinase, Crk, Grb2, and protein kinase C to FRS2 [10].…”

Section: Discussionmentioning

confidence: 99%

“…It is thought to play a critical role in early embryogenesis because knocking out the FRS2 gene in mice leads to embryonic lethality at E7-7.5 [1,2]. Quiescent FRS2 is membrane anchored through its N-terminal myristoylation site and is constitutively bound to FGFR through its PTB domain.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, PY of FRS2 is considered an early marker of FGF pathway activation. In addition, FRS2 has been reported to undergo PY in FGFR, NGFR, PDGFR, BDNFR, and VEGFR signaling pathways [2,[8][9][10][11], demonstrating its wide role in signal transduction.…”

Section: Introductionmentioning

confidence: 99%

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FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

Zhou

Feng

et al. 2009

Cell Res

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Section: Identification Of the Erk2-docking Site In Frs2supporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

Zhou

Feng

et al. 2009

Cell Res

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“…It is well established that Frs2 represents not only the critical mediator of Erk activation in FGF signaling but also a site of negative feedback (56,57). Erk phosphorylates Frs2 on multiple threonine residues, leading to diminished recruitment of Grb2 and down-regulation of Ras/Erk activity (57).…”

Section: Discussionmentioning

confidence: 99%

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Krejčı́

Masri

Salazar

et al. 2007

Journal of Biological Chemistry

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Activating mutations in fibroblast growth factor receptor 3 (FGFR3) cause several human dwarfisms characterized by diminished long bone growth (1). In cartilage, FGFR3 alters chondrocyte proliferation and differentiation by up-regulation of cell cycle inhibitors and stimulation of cartilage matrix degradation (2-5). The anti-proliferative action of FGF 2 signaling in cartilage contrasts with the usual mitogenic response of cells to FGF stimulus (6), but the molecular basis of this paradox remains unclear. Recently, Erk MAP kinase was found as a candidate for FGFR3-mediated inhibition of chondrocyte proliferation and differentiation (7-10).Protein kinase C (PKC) comprises a family of serine/threonine kinases that phosphorylate the consensus motif RXX(S/T)XR (11). The PKCs are further divided into three subfamilies based on sequence similarities and modes of activation. The conventional PKCs (PKC␣, -␤I, -␤II, and -␥) are activated by phosphatidylserine, diacylglycerol, and Ca 2ϩ , the novel PKCs (PKC␦, -⑀, -, and -) require only phosphatidylserine and diacylglycerol, and the atypical PKCs (aPKC; PKC and -) respond to phosphatidylserine alone (12). The PKC phosphorylation motif is present in many proteins (13), implicating PKCs as broad specificity protein kinases. PKCs are involved in numerous signaling events including activation of the Erk MAP kinase pathway. This is evident by potent Erk activation in cells treated with phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), which activates both conventional PKCs and novel PKCs through binding of their diacylglycerol site (14). In PMA-treated cells, PKCs target the Erk module at the level of both Raf-1 and MEK, through direct activatory phosphorylation or indirectly (15-21). Apart from PMA-mediated Erk activation, PKCs appear to be crucial for long term Erk activation by growth factors, including FGFs (20,[22][23][24][25], as well as for oncogenic .FGF signaling in chondrocytes leads to long term Ras/Erk activation, which appears to account for the growth inhibitory outcome of FGF treatment (8, 9). To date, little is known about chondrocyte properties of FGF signaling permitting prolonged Erk activity, although slow down-regulation of mutated FGFR3 appears to be involved (30,31).

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Docking Protein

2004

Encyclopedic Dictionary of Genetics, Genomics and Proteomics

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Critical role for the docking-protein FRS2α in FGF receptor-mediated signal transduction pathways

Cited by 264 publications

References 24 publications

FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

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