The carboxy-terminal sequence of p56lck can regulate p60c-src.

MacAuley, A; Cooper, Jonathan A.

doi:10.1128/mcb.8.8.3560

Cited by 14 publications

(11 citation statements)

References 34 publications

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“…The sites of aZ-stimulated 29.5-kDa fragment phosphory- lation were analyzed by exhaustive trypsin digestion (2,31). Major and minor phosphopeptides were detected (spots 1 and 2, respectively, Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural differences between repressed and derepressed forms of p60c-src.

MacAuley¹,

Cooper²

1989

Mol. Cell. Biol.

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The kinase activity of p60c-rc is derepressed by removal of phosphate from Tyr-527, mutation of this residue to Phe, or binding of a carboxy-terminal antibody. We have compared the structures of repressed and active p60c-src, using proteases. All forms of p60c.src are susceptible to proteolysis at the boundary between the amino-terminal region and the kinase domain, but there are several sites elsewhere that are more sensitive to trypsin digestion in repressed than in derepressed forms of p60csrc. The carboxy-terminal tail (containing Tyr-527) is more sensitive to digestion by pronase E and thermolysin when Tyr-527 is not phosphorylated. The kinase domain fragment released with trypsin has kinase activity. Relative to intact p60-src, the kinase domain fragment shows altered substrate specificity, diminished regulation by the phosphorylated carboxy terminus, and novel phosphorylation sites. The results identify parts of p60csrc that change conformation upon kinase activation and suggest functions for the amino-terminal region.

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Section: Resultsmentioning

confidence: 99%

Structural differences between repressed and derepressed forms of p60c-src.

MacAuley¹,

Cooper²

1989

Mol. Cell. Biol.

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“…Plasmids that contain ␤PDGF-R constructs were introduced as calcium phosphate precipitates into an NIH 3T3 packaging cell line, ⌿2, as previously described (46). After 48 h, a second NIH 3T3 packaging cell line, PA317, was infected with the ecotropic virus which was produced by the ⌿2 cells.…”

Section: Methodsmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Activation Is Insufficient for Growth Factor Receptor-Mediated PC12 Cell Differentiation

Vaillancourt

Heasley

Zamarripa

et al. 1995

Molecular and Cellular Biology

120

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When expressed in PC12 cells, the platelet-derived growth factor ␤ receptor (␤PDGF-R) mediates cell differentiation. Mutational analysis of the ␤PDGF-R indicated that persistent receptor stimulation of the Ras/Raf/mitogenactivated protein (MAP) kinase pathway alone was insufficient to sustain PC12 cell differentiation. PDGF receptor activation of signal pathways involving p60 c-src or the persistent regulation of phospholipase C␥ was required for PC12 cell differentiation. ␤PDGF-R regulation of phosphatidylinositol 3-kinase, the GTPase-activating protein of Ras, and the tyrosine phosphatase, Syp, was not required for PC12 cell differentiation. In contrast to overexpression of oncoproteins involved in regulating the MAP kinase pathway, growth factor receptor-mediated differentiation of PC12 cells requires the integration of other signals with the Ras/Raf/MAP kinase pathway.The platelet-derived growth factor receptor (PDGF-R) is a transmembrane polypeptide encoding an intrinsic tyrosine kinase in its intracellular domain. Two distinct PDGF-R genes encode either an ␣ (7, 42, 47) or a ␤ (6, 19, 73) subunit. Binding of PDGF (22) induces dimerization (23) and trans phosphorylation of the ␤PDGF-R on specific tyrosine residues (35). The phosphorylated receptor initiates a series of intracellular signals which ultimately lead to cell growth (12), differentiation (20), and chemotaxis (70) depending on the cellular context.A number of tyrosines on the intracellular domain of the ␤PDGF-R are phosphorylated upon activation of the receptor and serve as recognition sites for proteins which contain Src homology 2 (SH2) domains (57). For example, the ␤PDGF-R has been shown to associate with Src family tyrosine kinases p60 c-src , p59 fyn , and p62 c-yes (39) via juxtamembrane tyrosines 579 and 581, which are in vivo phosphorylation sites (50). The SH2 domain-containing proteins p46 and p52 (Shc proteins) bind to the ␤PDGF-R at multiple phosphotyrosines including tyrosine 581 and indirectly via association with other tyrosinephosphorylated proteins (74). Phosphorylation of tyrosines 740 and 751 is critical for association of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) with the ␤PDGF-R (2, 8, 29-31). Phosphorylated tyrosine 751 also binds Nck via its SH2 binding domain (52). The GTPase-activating protein (GAP) of Ras is tyrosine phosphorylated in response to PDGF and binds to the receptor at phosphorylated 33,49). The SH2-containing phosphotyrosine phosphatase, Syp, associates with phosphorylated tyrosine 1009 (34, 41). In addition, there is evidence which suggests that the adaptor protein, Grb2, associates with the ␤PDGF-R via tyrosine 716 (1) and indirectly through Syp (44). Phosphorylated tyrosine 1009 may also influence the binding of phospholipase C␥ (PLC␥) to tyrosine 1021 (28, 59). Mutational analysis of the ␤PDGF-R has demonstrated that phosphorylated tyrosines 740 and 751, which mediate association with PI3-K, and tyrosine 1021, which mediates association with PLC␥, are necessary for the transducti...

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“…The activity of several of these kinases was shown to be controlled by phosphorylation of a C-terminal tyrosine residue, and amino acid sequences surrounding the critical C-terminal tyrosine residue are well conserved among the different Src-like kinases (5,10). Moreover, a suppression of c-Src kinase activity was noted when residues 495-509 of Lck were substituted for the C-terminal peptide of c-Src, indicating a similarity in tertiary structures of these two C-terminal regions (34). To date, only CSK can phosphorylate the regulatory C-terminal tyrosine residue of c-Src.…”

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confidence: 99%

Molecular cloning and expression of chicken C-terminal Src kinase: lack of stable association with c-Src protein.

Sabe

Knudsen²,

Okada³

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Cloning and sequencing of chicken C-terminal Src kinase (CSK), a tyrosine kinase that phosphorylates the regulatory C-terminal tyrosine residue present on cytoplasmic tyrosine kinases of the Src family, demonstrated a high degree of interspecies conservation as well as src homology 2 and 3 domains N-terminal to the kinase domain. The lack of autophosphorylation sites distinguishes CSK from other tyrosine kinases. CSK is unique and does not belong to a gene family, suggesting that it may phosphorylate other members of the Src family of tyrosine kinases in addition to c-Src. Since complex formation between c-Src and CSK seemed a likely regulatory step in the control of c-Src kinase activity, such an asoation was investigated by immunoprecipitation and Western blotting as well as intracellular localization studies. Although some portions of CSK were found in a membrane fraction, no complex formation between CSK and c-Src was observed, suggesting that the src homology 2 domain ofCSK does not play a role in the direct interaction of c-Src.

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The carboxy-terminal sequence of p56lck can regulate p60c-src.

Abstract: A chimera containing the coding region for residues 1 to 516 of p60c-src and residues 495 to 509 (the carboxy terminus) of p56lck was constructed and expressed in mouse fibroblasts. The chimeric protein appeared to be phosphorylated and regulated in the same fashion as p60c-src.

Cited by 14 publications

References 34 publications

Structural differences between repressed and derepressed forms of p60c-src.

Structural differences between repressed and derepressed forms of p60c-src.

Mitogen-Activated Protein Kinase Activation Is Insufficient for Growth Factor Receptor-Mediated PC12 Cell Differentiation

Molecular cloning and expression of chicken C-terminal Src kinase: lack of stable association with c-Src protein.

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