Direct Association of Csk Homologous Kinase (CHK) with the Diphosphorylated Site Tyr568/570 of the Activated c-KIT in Megakaryocytes

Price, Daniel J.; Rivnay, Benjamin; Fu, Yue; Jiang, Shuxian; Avraham, Shalom; Avraham, Hava

doi:10.1074/jbc.272.9.5915

Cited by 84 publications

(72 citation statements)

References 18 publications

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“…Five tyrosine residues are located in the juxtamembrane region, out of which two are phosphorylated in vivo following SCF-stimulation. Tyr568 and Tyr570 have been shown by several groups to be phosphorylation sites (Kozlowski et al, 1998;Linnekin et al, 1997;Price et al, 1997;Timokhina et al, 1998). Linnekin et al (1997) could show that these tyrosine residues mediate binding of the Src family member Lyn in Mo7e cells, and demonstrate by an antisense approach and by the use of the Src inhibitor PP1 the importance of Src family kinases for Kit/SCFR mediated mitogenesis.…”

Section: Discussionmentioning

confidence: 95%

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

et al. 1999

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In this report we show that Tyr568 and Tyr570 are phosphorylated in vivo in the Kit/stem cell factor receptor (Kit/SCFR) following ligand-stimulation. By mutation of Tyr568 and Tyr570 to phenylalanine residues and expression of the mutated receptors in porcine aortic endothelial (PAE) cells, we could demonstrate a loss of activation of members of the Src family of tyrosine kinases when Tyr568 was mutated, while mutation of Tyr570 only led to a minor decrease in activation of Src family members. Mutation of both tyrosine residues led to a complete loss of Src family kinase activation. Phosphorylation of the adapter protein Shc by growth factor receptors provides association sites for Grb2-Sos, thereby activating the Ras/MAP kinase pathway. A much lowered degree of Shc phosphorylation, Ras and Erk2 activation and c-fos induction was seen in the Y568F mutant, while in the Y570F mutant these responses were less a ected. In contrast, the mitogenic response was only slightly reduced. In a mutant receptor with both Tyr568 and Tyr570 mutated to phenylalanine residues, no phosphorylation of Shc and no activation of Ras and Erk2 was seen in response to stem cell factor stimulation, very weak induction of c-fos was seen and the mitogenic response was severely depressed. These data show that Ras/MAP kinase activation and c-fos induction by Kit/SCFR are mediated by members of the Src family kinases. However, the mitogenic response is only to a minor extent dependent on Src kinase activity.

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Section: Discussionmentioning

confidence: 95%

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

et al. 1999

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“…We showed an absence of ERK-MAPK activation, and a constitutive activation of the p38-MAPK and AKT pathways. Interestingly, p38 has been slightly associated in the literature with proliferative signals and have very recently been identified as an important downstream signal in the KIT-dependent proliferation of erythroid progenitor cells (Price et al, 1997). Finally, it is interesting to note that constitutive p38-MAPK activation was correlated with an absence of ERK-MAPK activation in KD27-expressing cells.…”

Section: Difference In Receptor Features Between Wt and Kit Jmd Mutatmentioning

confidence: 89%

“…Members of the SRC family like FYN, LYN, but also the SRC-regulatory molecule MATK/ CHK, have been described to interact with the Tyr 567 residue (Linnekin et al, 1997;Price et al, 1997). This Tyr residue is also a hot spot for binding and a site of competition for interaction with other KIT substrates, and has thus been ascribed to the SHP2 phosphatase and is a part of a consensus sequence (Y 567 -V-Y 569 -I) of which the Tyr 569 is the SHP1 phosphatase binding site.…”

Section: Importance Of the Jmd In Kit Activationmentioning

confidence: 99%

Signal transduction by several KIT juxtamembrane domain mutations

et al. 2003

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Mutations of KIT receptor tyrosine kinase are found in the majority of patients with mastocytosis and in most gastrointestinal stromal tumors. Oncogenic KIT mutations in GISTs are located in the KIT juxtamembrane domain (JMD), while codon 816 in the KIT kinase domain is mutated in systemic mastocytosis. We describe and characterize a mutation in the KIT-JMD named KD27. We show that KD27 mutant is constitutively dimerized and phosphorylated. KD27 ectopic expression renders both the Ba/F3 cell line and primary cultures of bone marrow mast cells independent of cytokines for proliferation and cell survival. The classical signaling pathways activated by wild-type KIT upon ligand stimulation are constitutively activated by KD27 and other JMD mutations. However, a side-to-side comparison revealed differences between the wild-type and JMD mutations. First, in vitro kinase assays reveal a change in peptide substrate specificity. Second, STAT proteins are preferentially phosphorylated by KIT mutants. Third, inhibitors of KIT kinase are more efficient on JMD mutations than on WT KIT. We conclude that KD27 is a new oncogenic KIT mutation showing constitutive activation of downstream signaling pathways, and suggest that specific pathways are activated by oncogenic KIT.

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“…The peptide sequence that includes Tyr-567 and Tyr-569 has been shown to recruit several other SH2 domaincontaining proteins as follows: the tyrosine phosphatases SHP1 and SHP2 (38), members of Src family kinases (39), the Src kinase-negative regulators CSK homologous kinase/megacaryocyte-associated tyrosine kinase (40), and adaptor proteins of the APS (adaptor molecule containing PH and SHÉ domains)/SH2/ LNK family (41). Thus the di-tyrosine motif 567/569 appears to be a major docking site for the formation of protein complexes following KIT activation.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling

Bayle

Letard

Frank

et al. 2004

Journal of Biological Chemistry

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Suppressor of cytokine signaling (SOCS) proteins are a family of Src homology 2-containing adaptor proteins. Cytokine-inducible Src homology domain 2-containing protein, SOCS1, SOCS2, and SOCS3 have been implicated in the down-regulation of cytokine signaling. The function of SOCS4, 5, 6, and 7 are not known. KIT receptor signaling is regulated by protein tyrosine phosphatases and adaptor proteins. We previously reported that SOCS1 inhibited cell proliferation in response to stem cell factor (SCF Cytokines and growth factors regulate the survival, proliferation, differentiation, and migration of hematopoietic cells. Binding of these factors to transmembrane receptors induces receptor activation, which in turn results in the recruitment of signaling complexes in the vicinity of the plasma membrane. The kinetics and magnitude of signal transduction are tightly regulated by multiple mechanisms. Among proteins that modulate signaling, members of the suppressor of cytokine signaling (SOCS) 1 family have been shown to down-regulate the function of cytokines or growth factors (1-3).The eight members of the SOCS family, SOCS1-7 and CIS (cytokine-inducible Src homology domain (SH2)-containing protein), are structurally characterized by a SH2 domain followed by a conserved C-terminal motif, the SOCS box (4). The N-terminal region of SOCS proteins is variable both in length and in the primary amino acid sequence. Although many reports including knock-out studies shed light on the function of CIS (5, 6), SOCS1 (7, 8), SOCS2 (9, 10), and SOCS3 (11-13), very little is known regarding the function of SOCS4, SOCS5, SOCS6, and SOCS7.The mechanisms whereby CIS, SOCS1, and SOCS3 inhibit signaling by classical cytokine receptor (i.e. receptors without catalytic activity that associate with JAK tyrosine kinases) are the best characterized. All three are involved in the downregulation of the JAK/STAT pathway. SOCS1 has a dual function as a direct potent JAK kinase inhibitor (14 -17) and as a component of an E3 ubiquitin-ligase complex recruiting substrates to the protein degradation machinery (18 -20). SOCS3 also inhibits JAK activity but indirectly through recruitment to the cytokine receptors (1, 21). More recently, SOCS3 has been suggested to compete with SHP2 for the same binding sites on glycoprotein 130 (22, 23), erythropoietin receptor (21), and leptin receptor (24). CIS binds to cytokine receptors at STAT5-docking sites, which impairs recruitment of STAT5 to the receptor signaling complex and results in the down-regulation of STAT5 activation (6,25).Mice lacking SOCS6 have been generated, and they developed normally with the exception of a 10% reduction in weight compared with wild-type littermates (26). SOCS6 mRNA was induced by erythropoietin in cell lines (27) and was ubiquitously expressed in murine tissues (26). SOCS6 does not interact with JAKs, but the interaction with elongins B and C suggests that, as all SOCS proteins, it might be part of an E3 ubiquitin-ligase complex (28). Yet, there is no evidence so far suggesti...

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Direct Association of Csk Homologous Kinase (CHK) with the Diphosphorylated Site Tyr568/570 of the Activated c-KIT in Megakaryocytes

Abstract: The Csk homologous kinase (CHK), formerly MATK, has previously been shown to bind to activated c- KIT

Cited by 84 publications

References 18 publications

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

Signal transduction by several KIT juxtamembrane domain mutations

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling

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