HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by KARDINAL, C. Articles by FELLER, S. M. Search for Related Content PubMed PubMed Citation Articles by KARDINAL, C. Articles by FELLER, S. M.

Cell-penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients

CHRISTIAN KARDINAL^*, BIRGIT KONKOL^*,, AXEL SCHULZ, GUIDO POSERN^*, HUI LIN^§, KNUT ADERMANN, MANFRED EULITZ, ZEEV ESTROV^§, MOSHE TALPAZ^§, RALPH B. ARLINGHAUS^§ and STEPHAN M. FELLER^*1

^* Laboratory of Molecular Oncology, MSZ, Universität Würzburg, Germany;
Klinische Molekularbiologie und Tumorgenetik, GSF, Munich, Germany;
IPF, Hannover, Germany; and
^§ M. D. Anderson Cancer Center, Houston, Texas 77030, USA

¹Correspondence: Laboratory of Molecular Oncology, MSZ, Versbacher Str. 5, D-97078 Würzburg, Germany. E-mail stephan.feller{at}mail.uni-wuerzburg.de

Bcr-Abl contributes prominently to the development of most chronic myeloid leukemias (CMLs). Prior work has identified the adapter protein CRKL as a major substrate of the Bcr-Abl tyrosine kinase. CRKL can also bind via its first SH3 domain [SH3(1)] to specific sequences in Bcr-Abl. Cell-penetrating peptides were developed that bind with high affinity and selectivity to the SH3(1) domain of CRKL. They disrupt Bcr-Abl–CRKL complexes and strongly reduce the proliferation of primary CML blast cells and cell lines established from Bcr-Abl-positive patients. Activation-specific antibodies against phosphorylated MAP kinase (MAPK) showed that MAPK activity is down-regulated in blast cells treated with the CRKLSH3(1) blocker peptides. We conclude that the Bcr-Abl–CRKL complexes are largely dependent on the CRKLSH3(1) domain, that the central mitogenic cascade is down-regulated as a consequence of the disruption of CRKLSH3(1) interactions, and that CRKL therefore contributes to the proliferation of CML blast cells.—Kardinal, C., Konkol, B., Schulz, A., Posern, G., Lin, H., Adermann, K., Eulitz, M., Estrov, Z., Talpaz, M., Arlinghaus, R. B., Feller, S. M. Cell-penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients.

Key Words: CRKL • adapter protein • Bcr-Abl • MAP kinase (MAPK)

This article has been cited by other articles:

				C. I. Lopez, S. A. Belmonte, G. A. De Blas, and L. S. Mayorga Membrane-permeant Rab3A triggers acrosomal exocytosis in living human sperm FASEB J, December 1, 2007; 21(14): 4121 - 4130. [Abstract] [Full Text] [PDF]

				J. C. Sitko, C. I. Guevara, and N. A. Cacalano Tyrosine-phosphorylated SOCS3 Interacts with the Nck and Crk-L Adapter Proteins and Regulates Nck Activation J. Biol. Chem., September 3, 2004; 279(36): 37662 - 37669. [Abstract] [Full Text] [PDF]

				J. V. Melo, T. P. Hughes, and J. F. Apperley Chronic Myeloid Leukemia Hematology, January 1, 2003; 2003(1): 132 - 152. [Abstract] [Full Text] [PDF]

				H. Nishihara, M. Maeda, A. Oda, M. Tsuda, H. Sawa, K. Nagashima, and S. Tanaka DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines Blood, December 1, 2002; 100(12): 3968 - 3974. [Abstract] [Full Text] [PDF]

				B. Hemmeryckx, A. van Wijk, A. Reichert, V. Kaartinen, Ron de Jong, P. K. Pattengale, I. Gonzalez-Gomez, J. Groffen, and N. Heisterkamp Crkl Enhances Leukemogenesis in BCR/ABL P190 Transgenic Mice Cancer Res., February 1, 2001; 61(4): 1398 - 1405. [Abstract] [Full Text]