The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells

Agata Klejman; Steven J. Schreiner; Malgorzata Nieborowska-Skorska; Artur Slupianek; Matthew Wilson; Thomas E. Smithgall; Tomasz Skorski

doi:10.1093/emboj/cdf562

The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells

Agata Klejman, Steven J. Schreiner, Malgorzata Nieborowska-Skorska, Artur Slupianek, Matthew Wilson, Thomas E. Smithgall, Tomasz Skorski

Temple University

Research output: Contribution to journal › Article › peer-review

190 Scopus citations

Abstract

Signal transducer and activator of transcription 5 (STAT5) is constitutively activated by BCR/ABL, the oncogenic tyrosine kinase responsible for chronic myelogenous leukemia. The mechanism of BCR/ABL-mediated STAT5 activation is unknown. We show here that the BCR/ABL SH3 and SH2 domains interact with hematopoietic cell kinase (Hck), leading to the stimulation of Hck catalytic activity. Active Hck phosphorylated STAT5B on Tyr699, which represents an essential step in STAT5B stimulation. Moreover, a kinase-dead Hck mutant and Hck inhibitor PP2 abrogated BCR/ABL-dependent activation of STAT5 and elevation of expression of STAT5 downstream effectors A1 and pim-1. These data identify a novel BCR/ ABL-Hck-STAT5 signaling pathway, which plays an important role in BCR/ABL-mediated transformation of myeloid cells.

Original language	English
Pages (from-to)	5766-5774
Number of pages	9
Journal	EMBO Journal
Volume	21
Issue number	21
DOIs	https://doi.org/10.1093/emboj/cdf562
State	Published - Nov 1 2002

Keywords

ABL
Activation
BCR
Hck
Pathway
STAT5

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title = "The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells",

abstract = "Signal transducer and activator of transcription 5 (STAT5) is constitutively activated by BCR/ABL, the oncogenic tyrosine kinase responsible for chronic myelogenous leukemia. The mechanism of BCR/ABL-mediated STAT5 activation is unknown. We show here that the BCR/ABL SH3 and SH2 domains interact with hematopoietic cell kinase (Hck), leading to the stimulation of Hck catalytic activity. Active Hck phosphorylated STAT5B on Tyr699, which represents an essential step in STAT5B stimulation. Moreover, a kinase-dead Hck mutant and Hck inhibitor PP2 abrogated BCR/ABL-dependent activation of STAT5 and elevation of expression of STAT5 downstream effectors A1 and pim-1. These data identify a novel BCR/ ABL-Hck-STAT5 signaling pathway, which plays an important role in BCR/ABL-mediated transformation of myeloid cells.",

keywords = "ABL, Activation, BCR, Hck, Pathway, STAT5",

author = "Agata Klejman and Schreiner, {Steven J.} and Malgorzata Nieborowska-Skorska and Artur Slupianek and Matthew Wilson and Smithgall, {Thomas E.} and Tomasz Skorski",

year = "2002",

month = nov,

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doi = "10.1093/emboj/cdf562",

language = "English",

volume = "21",

pages = "5766--5774",

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TY - JOUR

T1 - The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells

AU - Klejman, Agata

AU - Schreiner, Steven J.

AU - Nieborowska-Skorska, Malgorzata

AU - Slupianek, Artur

AU - Wilson, Matthew

AU - Smithgall, Thomas E.

AU - Skorski, Tomasz

PY - 2002/11/1

Y1 - 2002/11/1

N2 - Signal transducer and activator of transcription 5 (STAT5) is constitutively activated by BCR/ABL, the oncogenic tyrosine kinase responsible for chronic myelogenous leukemia. The mechanism of BCR/ABL-mediated STAT5 activation is unknown. We show here that the BCR/ABL SH3 and SH2 domains interact with hematopoietic cell kinase (Hck), leading to the stimulation of Hck catalytic activity. Active Hck phosphorylated STAT5B on Tyr699, which represents an essential step in STAT5B stimulation. Moreover, a kinase-dead Hck mutant and Hck inhibitor PP2 abrogated BCR/ABL-dependent activation of STAT5 and elevation of expression of STAT5 downstream effectors A1 and pim-1. These data identify a novel BCR/ ABL-Hck-STAT5 signaling pathway, which plays an important role in BCR/ABL-mediated transformation of myeloid cells.

AB - Signal transducer and activator of transcription 5 (STAT5) is constitutively activated by BCR/ABL, the oncogenic tyrosine kinase responsible for chronic myelogenous leukemia. The mechanism of BCR/ABL-mediated STAT5 activation is unknown. We show here that the BCR/ABL SH3 and SH2 domains interact with hematopoietic cell kinase (Hck), leading to the stimulation of Hck catalytic activity. Active Hck phosphorylated STAT5B on Tyr699, which represents an essential step in STAT5B stimulation. Moreover, a kinase-dead Hck mutant and Hck inhibitor PP2 abrogated BCR/ABL-dependent activation of STAT5 and elevation of expression of STAT5 downstream effectors A1 and pim-1. These data identify a novel BCR/ ABL-Hck-STAT5 signaling pathway, which plays an important role in BCR/ABL-mediated transformation of myeloid cells.

KW - ABL

KW - Activation

KW - BCR

KW - Hck

KW - Pathway

KW - STAT5

UR - http://www.scopus.com/inward/record.url?scp=0036847027&partnerID=8YFLogxK

U2 - 10.1093/emboj/cdf562

DO - 10.1093/emboj/cdf562

M3 - Article

C2 - 12411494

SN - 0261-4189

VL - 21

SP - 5766

EP - 5774

JO - EMBO Journal

JF - EMBO Journal

IS - 21

ER -

The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells

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Keywords

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