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Molecular and Cellular Biology, February 2001, p. 1077-1088, Vol. 21, No. 4
Laboratory of Molecular Oncology, IRCM,
Montréal, Québec, Canada H2W 1R71;
McGill Cancer Centre2 and
Departments of Medicine4 and
Biochemistry,5 McGill University,
Montréal, Québec, Canada H3G 1Y6; and
Department of Medicine, Mount Sinai School of Medicine, New
York, New York 100293
Received 14 September 2000/Returned for modification 24 October
2000/Accepted 10 November 2000
The protein tyrosine kinase (PTK) Csk is a potent negative
regulator of several signal transduction processes, as a consequence of
its exquisite ability to inactivate Src-related PTKs. This function
requires not only the kinase domain of Csk, but also its Src homology 3 (SH3) and SH2 regions. We showed previously that the Csk SH3 domain
mediates highly specific associations with two members of the PEP
family of nonreceptor protein tyrosine phosphatases (PTPs), PEP and
PTP-PEST. In comparison, the Csk SH2 domain interacts with several
tyrosine phosphorylated molecules, presumed to allow targetting of Csk
to sites of Src family kinase activation. Herein, we attempted to
understand better the regulation of Csk by identifying ligands for its
SH2 domain. Using a modified yeast two-hybrid screen, we uncovered the
fact that Csk associates with PTP-HSCF, the third member of the PEP
family of PTPs. This association was documented not only in yeast cells
but also in a heterologous mammalian cell system and in
cytokine-dependent hemopoietic cells. Surprisingly, the Csk-PTP-HSCF
interaction was found to be mediated by the Csk SH2 domain and two
putative sites of tyrosine phosphorylation in the noncatalytic portion of PTP-HSCF. Transfection experiments indicated that Csk and PTP-HSCF synergized to inhibit signal transduction by Src family kinases and
that this cooperativity was dependent on the domains mediating their
association. Finally, we obtained evidence that PTP-HSCF inactivated
Src-related PTKs by selectively dephosphorylating the positive
regulatory tyrosine in their kinase domain. Taken together, these
results demonstrate that part of the function of the Csk SH2 domain is
to mediate an inducible association with a PTP, thereby engineering a
more efficient inhibitory mechanism for Src-related PTKs. Coupled with
previously published observations, these data also establish that Csk
forms complexes with all three known members of the PEP family.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.4.1077-1088.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
SH2 Domain-Mediated Interaction of Inhibitory Protein Tyrosine
Kinase Csk with Protein Tyrosine Phosphatase-HSCF
*
Corresponding author. Mailing address: Laboratory of
Molecular Oncology, IRCM, 110 Pine Ave. West, Montréal,
Québec, Canada H2W 1R7. Phone: (514) 987-5561. Fax: (514)
987-5562. E-mail: veillea{at}ircm.qc.ca.
Molecular and Cellular Biology, February 2001, p. 1077-1088, Vol. 21, No. 4
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.4.1077-1088.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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