Dataset Information

Reciprocal regulation of Abl and receptor tyrosine kinases.

ABSTRACT: Previously, we showed that Abl kinases (c-Abl, Arg) are activated downstream of PDGF in a manner dependent on Src kinases and PLC-gamma1, and promote PDGF-mediated proliferation and migration of fibroblasts. We additionally demonstrated that Abl kinases bind directly to PDGFR-beta via their SH2 domains.In this study, we extend these findings by demonstrating that Abl kinases also are activated downstream of aPDGF autocrine growth loop in glioblastoma cells, indicating that the PDGFR-Abl signaling pathway also is likely to be important in glioblastoma development and/or progression.We recently showed that Abl kinases are highly active in many breast cancer cell lines, and the Her-2 receptor tyrosine kinase contributes to c-Abl and Arg kinase activation. In this study, we show that Abl kinase SH2 domains bind directly to Her-2, and like PDGFR-beta , Her-2 directly phosphorylates c-Abl. Previously, we demonstrated that PDGFR-beta directly phosphorylates Abl kinases in vitro, and Abl kinases reciprocally phosphorylate PDGFR-beta . Here, we show that PDGFR-beta-phosphorylation of Abl kinases has functional consequences as PDGFR-beta phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases. Moreover, PDGFR-beta phosphorylates Arg on two additional unique sites whose function is unknown. Importantly, we also show that Abl-dependent phosphorylation of PDGFR-beta has functional and biological significances. c-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis. These data are exciting as they indicate that Abl kinases not only are activated by PDGFR and promote PDGFR-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off PDGFR-mediated chemotaxis.

SUBMITTER: Srinivasan D

PROVIDER: S-EPMC2701649 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Reciprocal regulation of Abl and receptor tyrosine kinases.

Srinivasan Divyamani D Kaetzel David M DM Plattner Rina R

Cellular signalling 20090309 7

Previously, we showed that Abl kinases (c-Abl, Arg) are activated downstream of PDGF in a manner dependent on Src kinases and PLC-gamma1, and promote PDGF-mediated proliferation and migration of fibroblasts. We additionally demonstrated that Abl kinases bind directly to PDGFR-beta via their SH2 domains.In this study, we extend these findings by demonstrating that Abl kinases also are activated downstream of aPDGF autocrine growth loop in glioblastoma cells, indicating that the PDGFR-Abl signalin ...[more]

PMID: 19275932

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Project description:Eph receptors play pivotal roles in the axon guidance of retinal ganglion cells (RGCs) at the optic chiasm and the establishment of the topographic retinocollicular map. We previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) is specifically involved in the control of retinotectal projections in chicks through the dephosphorylation of EphA and EphB receptors. We subsequently revealed that all the mouse R3 subfamily members (PTPRB, PTPRH, PTPRJ, and PTPRO) of the receptor protein tyrosine phosphatase (RPTP) family inhibited Eph receptors as their substrates in cultured mammalian cells. We herein investigated the functional roles of R3 RPTPs in the projection of mouse retinal axon of both sexes. Ptpro and Ptprj were expressed in mouse RGCs; however, Ptprj expression levels were markedly higher than those of Ptpro Consistent with their expression levels, Eph receptor activity was significantly enhanced in Ptprj-knock-out (Ptprj-KO) retinas. In Ptprj-KO and Ptprj/Ptpro-double-KO (DKO) mice, the number of retinal axons that projected ipsilaterally or to the contralateral eye was significantly increased. Furthermore, retinal axons in Ptprj-KO and DKO mice formed anteriorly shifted ectopic terminal zones in the superior colliculus (SC). We found that c-Abl (Abelson tyrosine kinase) was downstream of ephrin-Eph signaling for the repulsion of retinal axons at the optic chiasm and in the SC. c-Abl was identified as a novel substrate for PTPRJ and PTPRO, and the phosphorylation of c-Abl was upregulated in Ptprj-KO and DKO retinas. Thus, PTPRJ regulates retinocollicular projections in mice by controlling the activity of Eph and c-Abl kinases.SIGNIFICANCE STATEMENT Correct retinocollicular projection is a prerequisite for proper vision. Eph receptors have been implicated in retinal axon guidance at the optic chiasm and the establishment of the topographic retinocollicular map. We herein demonstrated that protein tyrosine phosphatase receptor type J (PTPRJ) regulated retinal axonal projections by controlling Eph activities. The retinas of Ptprj-knock-out (KO) and Ptpro/Ptprj double-KO mice exhibited significantly enhanced Eph activities over those in wild-type mice, and their axons showed defects in pathfinding at the chiasm and retinocollicular topographic map formation. We also revealed that c-Abl (Abelson tyrosine kinase) downstream of Eph receptors was regulated by PTPRJ. These results indicate that the regulation of the ephrin-Eph-c-Abl axis by PTPRJ plays pivotal roles in the proper central projection of retinal axons during development.

Dataset Information

Reciprocal regulation of Abl and receptor tyrosine kinases.

Publications

Reciprocal regulation of Abl and receptor tyrosine kinases.

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