Uncoupling of Grb2 from the Met Receptor In Vivo Reveals Complex Roles in Muscle Development

Maina, Flavio; Casagranda, Franca; Audero, Enrica; Simeone, Antonio; Comoglio, Paolo M.; Klein, Rüdiger; Ponzetto, Antonio

doi:10.1016/s0092-8674(00)81372-0

Cited by 294 publications

(276 citation statements)

References 37 publications

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“…Accordingly, the constitutively active oncogenic counterpart of the Met receptor (Tpr ± Met) transforms ®broblasts at high e ciency, and renders them highly metastatic (Park et al, 1986;Giordano et al, 1997). Met signaling and transformation depend on ligand-induced phosphorylation of two carboxy-terminal docking sites of mixed speci®city (Y 1349 /VHVNATY 1356 /VNV, Ponzetto et al, 1994;Fixman et al, 1995;Maina et al, 1996). These phosphotyrosines are responsible for recruiting a number of SH2-containing e ectors, including p85 (the regulatory subunit of PI 3-kinase) and the Grb2 adaptor (Ponzetto et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…These tyrosine residues are part of a consensus sequence (YVH/NV) which mediates coupling of the receptor with several e ectors, including the Grb2/SoS complex (Ponzetto et al, 1994;Fixman et al, 1995), the p85 regulatory subunit of PI-3-kinase (Ponzetto et al, 1993), Stat-3 (Boccaccio et al, 1998), and the multiadaptor protein Gab1 (Weidner et al, 1996;Bardelli et al, 1997b;Nguyen et al, 1997). Grb2, in particular, requires an Asn in the +2 position for binding, and is thus linked to the receptor via the Y 1356 VNV motif Maina et al, 1996;Fixman et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

et al. 1999

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The Met tyrosine kinase ± the HGF receptor ± induces cell transformation and metastasis when constitutively activated. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines which act as docking sites for a number of SH2-containing molecules. These include Grb2 and p85 which couple the receptor, respectively, with Ras and PI 3-kinase. We previously showed that a Met mutant designed to obtain preferential coupling with Grb2 (Met 2xGrb2 ) is permissive for motility, increases transformation, but ± surprisingly ± is impaired in causing invasion and metastasis. In this work we used Met mutants optimized for binding either p85 alone (Met 2xPI3K ) or p85 and Grb2 (Met P13K/Grb2 ) to evaluate the relative importance of Ras and PI 3-kinase as downstream e ectors of Met. Met 2xPI3K was competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, Met P13K/Grb2 induced motility, transformation, invasion and metastasis as e ciently as wild type Met. Furthermore, the expression of constitutively active PI 3-kinase in cells transformed by the Met 2xGrb2 mutant, fully rescued their ability to invade and metastasize. These data point to a central role for PI 3-kinase in Met-mediated invasiveness, and indicate that simultaneous activation of Ras and PI 3-kinase is required to unleash the Met metastatic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

et al. 1999

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“…A number of observations suggest that c-met is a downstream target of pax3, already clearly implicated in human alveolar RMS. As in pax3-de®cient Splotch mice, myogenic precursor cells in c-met-de®cient mice cannot populate the limbs, and limb and diaphragm muscles fail to develop (Bober et al, 1994;Goulding et al, 1994;Bladt et al, 1995;Maina et al, 1996). Expression of c-met in lateral dermomyotome is downregulated in Splotch mice (Daston et al, 1996;Epstein et al, 1996;Yang et al, 1996), although c-metindependent muscular anomalies have been described in this mutant as well (Dietrich et al, 1999).…”

Section: The Patched/pax/met Connectionmentioning

confidence: 99%

Rhabdomyosarcoma – working out the pathways

1999

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Rhabdomyosarcomas constitute a collection of childhood malignancies thought to arise as a consequence of regulatory disruption of skeletal muscle progenitor cell growth and di erentiation. Our understanding of the pathogenesis of this neoplasm has recently bene®ted from the study of normal and malignant myogenic cells in vitro, facilitating the identi®cation of diagnostic cytogenetic markers and the elucidation of mechanisms by which myogenesis is regulated. It is now appreciated that the delicate balance between proliferation and di erentiation, mutually exclusive yet intimately associated processes, is normally controlled in large part through the action of a multitude of growth factors, whose signals are interpreted by members of the MyoD family of helix ± loop ± helix proteins, and key regulatory cell cycle factors. The latter have proven to be frequent targets of mutational events that subvert myogenesis and promote the development of rhabdomyosarcoma. Although signi®cant progress has been made in the treatment of rhabdomyosarcoma, patients presenting with metastatic disease or certain high risk features are still faced with a dismal prognosis. Only now are genetically engineered mouse models becoming available that are certain to provide fresh insights into the molecular/genetic pathways by which rhabdomyosarcomas arise and progress, and to suggest novel avenues of therapeutic opportunity.

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“…Skeletal muscle progenitor cells that form limb, tongue, and diaphragm musculature delaminate from the epithelial dermomyotome of the somites by an epithelial-to-mesenchymal transition and migrate to their final destination where they complete differentiation (Christ and Brand-Saberi, 2002). Loss of HGF or Met function in the mouse results in defective delamination and migration of these muscle progenitors from the dermomyotome and, therefore, they are absent from their target regions Maina et al, 1996;Dietrich et al, 1999). Previous work using zebrafish has also demonstrated that Met signaling is required for muscle progenitor cell migration from the somites to form fin hypaxial muscle (Haines et al, 2004).…”

Section: Introductionmentioning

confidence: 99%