Csk-binding Protein Mediates Sequential Enzymatic Down-regulation and Degradation of Lyn in Erythropoietin-stimulated Cells

Ingley, Evan; Schneider, Jessica R.; Payne, Christine J.; McCarthy, David; Harder, Kenneth W.; Hibbs, Margaret L.; Klinken, S. Peter

doi:10.1074/jbc.m602637200

Cited by 40 publications

(61 citation statements)

References 58 publications

(77 reference statements)

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“…PAG was originally identified as a Csk-binder, implicating phosphorylation of Tyr317 on PAG, but it contains eight additional SFK phosphorylation sites, allowing interaction with SH2-containing proteins, two poly-Pro motifs for interaction with SH3-containing proteins and two palmitoylation sites implicated in lipid rafts localization (Horejsi et al, 2004). Known interactors include the E3-ligase SOCS1 (Ingley et al, 2006), the negative Ras regulator RasGAP (Smida et al, 2007) and SFK themselves Solheim et al, 2008;Tauzin et al, 2008). Besides, we recently reported an unanticipated interaction between PAG N-terminus and the Neu-3 sialidase (Veracini et al, 2008), controlling lipid raft properties (Miyagi et al, 2008).…”

Section: Discussionmentioning

confidence: 89%

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

et al. 2009

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The nonreceptor tyrosine kinases of the Src family (SFK) are frequently deregulated in human colorectal cancer (CRC), and they have been implicated in tumour growth and metastasis. How SFK are activated in this cancer has not been clearly established. Here, we show that the SFK-dependent invasion is induced by inactivation of the negative regulator C-terminal Src kinase, Csk. While the level of Csk was inconsistent with SFK activity in colon cancer cells, its membrane translocation, needed for efficient regulation of membrane-localized SFK activity, was impaired. Accordingly, Csk downregulation did not affect SFK oncogenic activity in these cells, whereas expression of a membrane-localized form of this kinase affected their invasive activity. Downregulation of the transmembrane and rafts-localized Csk-binding protein/ phosphoprotein associated with glycosphingolipid-enriched microdomain (PAG), was instrumental for the cytoplasmic accumulation of Csk. Re-expression of PAG in cells from late-stage CRC inhibited SFK invasive activity in a Cskdependent manner. Conversely, inactivation of its residual expression in early-stage CRC cells promoted SFK invasive activity. Finally, this mechanism was specific to CRC as Csk coupling to SFK was readily detected in breast cancer cells. Therefore, Csk mis-localization defines a novel mechanism for SFK oncogenic activation in CRC cells.

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Section: Discussionmentioning

confidence: 89%

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

et al. 2009

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“…Lyn is the major src kinase that can be either activated by BCR or inactivated by Csk (Ingley et al, 2006). Expression of full length K15 or K15 cytoplasmic region as a CD8 chimera in BJAB was enough to activate the Lyn kinase dramatically, as evidenced by increased tyrosine phosphorylation of 53kDa in K15 cell extracts compared to the vector control.…”

Section: Discussionmentioning

confidence: 99%

Multi-transmembrane protein K15 of Kaposi's sarcoma-associated herpesvirus targets Lyn kinase in the membrane raft and induces NFAT/AP1 activities

Cho

Choi

2008

Exp Mol Med

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Viral proteins of γ-2 herpesviruses, such as LMP2A of Epstein Barr virus (EBV) and Tip of herpesvirus saimiri (HVS) dysregulate lymphocyte signaling by interacting with Src family kinases. K15 open reading frame of Kaposi's sarcoma associated herpesvirus (KSHV), located at the right end of the viral genome, encodes several splicing variants differing in numbers of transmembrane domains. Previously, we demonstrated that the cytoplasmic tail of the K15 protein interfered with B cell receptor signal transduction to cellular tyrosine phosphorylation and calcium mobilization. However, the detailed mechanism underlying this phenomenon was not understood. In the C-terminal cytoplasmic region of K15, putative binding domains for Src-SH2 and -SH3 were identified. In this study, we attempted to characterize these modular elements and cellular binding protein(s) by GST pull down and co-immunoprecipitation assays. These studies revealed that K15 interacted with the major B cell tyrosine kinase Lyn. In vitro kinase and transient co-expression assays showed that the expression of K15 protein resulted in activation of Lyn kinase activity. In addition, GST pull down assay suggested that the SH2 domain of Lyn alone was necessary for interaction with the C-terminal SH2B (YEEV) of K15, but the addition of Lyn SH3 to the SH2 domain increases the binding affinity to K15 protein. The data from luciferase assays indicate that K15 expression in BJAB cells induced NFAT and AP1 activities. The tyrosine residue in the C-terminal end of K15 required for the Lyn interaction appeared to be essential for NFAT/AP1 activation, highlighting the significance of the C-terminal SH2B of K15 as a modular element in interfering with B lymphocyte signaling through interaction with Lyn kinase.

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“…In erythroid cells, phosphorylation of PAG is dependent on the kinase Lyn, and the second proline-rich region has already been identified as a binding site for Lyn in a yeast two-hybrid screen (22). To locate the FynT SH3 domain-interacting site on PAG, we performed a peptide walk by synthesizing a SPOT peptide array on nitrocellulose membranes consisting of overlapping 20-mer peptides at 3-amino acid intervals.…”

Section: Interaction Of Fynt With Pag In Mammalian Cells-previous Repmentioning

confidence: 99%

“…Interaction via the FynT SH3 domain has also been discussed, since mutations of PAG tyrosines have been shown not to abolish FynT association completely (18). Interestingly, phosphorylation of PAG in mast cells is dependent on the association with the SFK Lyn (19 -21), and this interaction has recently been shown to involve concomitant, dual binding of Lyn SH3 and SH2 domains (22).…”

mentioning

confidence: 99%

Regulation of FynT Function by Dual Domain Docking on PAG/Cbp

Solheim

Torgersen

Taskén

et al. 2008

Journal of Biological Chemistry

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Csk-binding Protein Mediates Sequential Enzymatic Down-regulation and Degradation of Lyn in Erythropoietin-stimulated Cells

Cited by 40 publications

References 58 publications

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

Multi-transmembrane protein K15 of Kaposi's sarcoma-associated herpesvirus targets Lyn kinase in the membrane raft and induces NFAT/AP1 activities

Regulation of FynT Function by Dual Domain Docking on PAG/Cbp

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