Regulation of growth factor activation by proteoglycans: What is the role of the low affinity receptors?

Schlessinger, Joseph; Lax, Irit; Lemmon, Mark A.

doi:10.1016/0092-8674(95)90112-4

Cited by 466 publications

(307 citation statements)

References 19 publications

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“…It is interesting to note that BNIP-2 binds strongly to the region on Cdc42 that contains both the effector binding site as well as the nucleotide binding site. 3 Although a more defined site on Cdc42 that BNIP-2 binds to is yet to be mapped, it is tempting to suggest that the binding to this region can compete with the binding of some of these effectors or Cdc42GAP, as seen in our competition studies. Therefore, BNIP-2 and other Cdc42-binding molecules could potentially be regulating the binding of each other, either negatively by mutual competition or positively by augmenting the complex formation through a locatory sequence.…”

Section: Tyrosine Phosphorylation Of Bnip-2 Prevents Its Binding To mentioning

confidence: 83%

“…FGFs induce their biological responses by binding to and activating a family of cell surface receptors with intrinsic tyrosine kinase activity (2). Dimerization of FGF receptors is essential for kinase activation and for receptor autophosphorylation and requires the concerted action of FGF together with soluble or cell-surface heparan sulfate proteoglycans (3).…”

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confidence: 99%

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Tyrosine Phosphorylation of the Bcl-2-associated Protein BNIP-2 by Fibroblast Growth Factor Receptor-1 Prevents Its Binding to Cdc42GAP and Cdc42

Low

Lim

et al. 1999

Journal of Biological Chemistry

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Fibroblast growth factor (FGF) receptor tyrosine kinases are involved in the regulation of cell growth, development, and differentiation in a variety of tissues. To isolate potential signaling molecules in the FGF signaling pathway, we have initiated a yeast two-hybrid screening using the cytosolic domain of FGF receptor-1 (Flg). Here we report the identification of BNIP-2, a previously cloned Bcl-2-and adenovirus E1B-associated protein, as a putative substrate of the receptor. When cotransfected in 293T cells, BNIP-2 was tyrosine-phosphorylated via Flg, but their interaction was transient and could only be seen by "capture" experiments with catalytically inert kinase mutants. When responsive cells were challenged with basic FGF, endogenous tyrosine-phosphorylated BNIP-2 could be precipitated with a BNIP-2 antibody. In addition, the recombinant BNIP-2 expressed in bacteria could be phosphorylated by active Flg in vitro. BNIP-2 shares a region of homology with the noncatalytic domain of Cdc42GAP, a GTPase-activating protein for the small GTP-binding molecule, Cdc42. We show here that BNIP-2 and Cdc42GAP could directly bind to each other and they also compete for the binding to the same target, Cdc42. Unexpectedly, BNIP-2, either produced as a bacterial recombinant protein or expressed in 293T cells, could stimulate the intrinsic GTPase activity of Cdc42. In all cases, tyrosine phosphorylation of BNIP-2 severely impaired its association with Cdc42GAP and its induced GTPase-activating protein-like activity toward Cdc42. These findings should allow us to further characterize the integration of signaling between receptor tyrosine kinases, GTPbinding molecules, and apoptotic pathways.

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Section: Tyrosine Phosphorylation Of Bnip-2 Prevents Its Binding To mentioning

confidence: 83%

mentioning

confidence: 99%

Tyrosine Phosphorylation of the Bcl-2-associated Protein BNIP-2 by Fibroblast Growth Factor Receptor-1 Prevents Its Binding to Cdc42GAP and Cdc42

Low

Lim

et al. 1999

Journal of Biological Chemistry

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“…By analogy to the blood coagulation system, we may imagine that cell surface HSPGs use a reduction-in-dimensionality strategy to increase the rate of encounter between growth factors and their receptors. Indeed, such a possibility has been raised explicitly (Schlessinger et al, 1995). It is important to recognize, however, that the mechanism worked out for GAG catalysis of the encounter of AT and thrombin will most likely not be applicable in the growth factor-receptor case.…”

Section: Catatytic Rotes Of Hspgs Are Precedented In the Control Of Bmentioning

confidence: 99%

Proteoglycans: Master regulators of molecular encounter?

Lander

1998

Matrix Biology

103

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“…Still, both are found complexed to low a nity proteoglycan receptors of the extracellular matrix (EM), and both are widely distributed in embryonic, adult and tumor tissues. Mobilization of the dormant FGF-1 and -2 leads to their activation and facilitates binding to high a nity tyrosine kinase receptors (Aviezer et al, 1994;Brem and Klagsbrun, 1993;Schlessinger et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Expression of a binding protein for FGF is associated with epithelial development and skin carcinogenesis

et al. 1997

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Fibroblast growth factors (FGF)-1 and -2 are found in most embryonic and adult normal and tumor tissues, where they are immobilized in the extracellular matrix (EM). Mobilization of these FGFs is part of a tightly controlled process resulting in the activation of higha nity receptors. Recently, we have shown that a novel human FGF-binding protein (FGF-BP) mediates the release of immobilized FGF-2 from the EM. Here we isolated genomic and cDNA clones of the mouse FGF-BP homologue and studied its expression during embryonic development and skin carcinogenesis. The murine gene contains two exons that generate a 1.2 kb mRNA and predicts an 18 kDa secreted protein that is 63% identical to its human homologue. FGF-BP mRNA expression during embryogenesis is restricted to skin, intestine and lung. In the developing skin, FGF-BP expression starts at embryonic day 9, reaches peak levels perinatally and is downregulated during postnatal development. Develepment regulation in the intestine is similar, but in lungs and ovaries high expression was also observed in the adult. FGF-BP mRNA expression in the adult skin is dramatically increased during early stages of carcinogen-induced transformation in vivo and by rasactivation in vitro. Finally, mouse FGF-BP binds to FGF-2 and can function as a modulator of FGF in FGFresponsive cells. Our results suggest a potential function of FGF-BP during development and tumorigenesis.

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Regulation of growth factor activation by proteoglycans: What is the role of the low affinity receptors?

Cited by 466 publications

References 19 publications

Tyrosine Phosphorylation of the Bcl-2-associated Protein BNIP-2 by Fibroblast Growth Factor Receptor-1 Prevents Its Binding to Cdc42GAP and Cdc42

Tyrosine Phosphorylation of the Bcl-2-associated Protein BNIP-2 by Fibroblast Growth Factor Receptor-1 Prevents Its Binding to Cdc42GAP and Cdc42

Proteoglycans: Master regulators of molecular encounter?

Expression of a binding protein for FGF is associated with epithelial development and skin carcinogenesis

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