The phosphatidylinositol 3' kinase pathway is required for the survival signal of leukocyte tyrosine kinase.

Abstract:

:Leukocyte tyrosine kinase (LTK) is a receptor tyrosine kinase which belongs to the insulin receptor superfamily and is mainly expressed in pre-B lymphocytes and neuronal tissues. Recently, we demonstrated that LTK utilizes Shc and IRS-1 as two major substrates and while both equally activate the Ras pathway, only IRS-1 suppresses apoptosis of hematopoietic cells, suggesting the existence of another unidentified signaling pathway downstream of IRS-1, which is relevant to the anti-apoptotic activity. In the present study, we found that wortmannin, a specific inhibitor of phosphatidylinositol 3' (PI3)-kinase, abolished the survival effects of LTK. Although c-Cbl is found to be phosphorylated by LTK and therefore is a second candidate linking LTK with the PI3-kinase pathway along with IRS-1, we found that the p85 subunit of PI3 kinase directly binds to tyrosine 753 of LTK, which is located within a YXXM motif, a consensus binding amino acid sequence for the SH2 domain of p85, but fails to bind to IRS-1 or c-Cbl. Ba/F3 cells which stably express the EGF receptor-LTK chimeric receptor carrying a mutation at tyrosine 753 fell into apoptotic death even in the presence of EGF, indicating that the PI3 kinase pathway is required for the survival effects of LTK.

journal_name

Oncogene

journal_title

Oncogene

authors

Ueno H,Honda H,Nakamoto T,Yamagata T,Sasaki K,Miyagawa K,Mitani K,Yazaki Y,Hirai H

doi

10.1038/sj.onc.1201153

subject

Has Abstract

pub_date

1997-06-26 00:00:00

pages

3067-72

issue

25

eissn

0950-9232

issn

1476-5594

journal_volume

14

pub_type

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