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Molecular and Cellular Biology, May 2005, p. 3690-3703, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3690-3703.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases

Dirk-E. Schmidt-Arras,1 Annette Böhmer,1 Boyka Markova,1 Chunaram Choudhary,2 Hubert Serve,2 and Frank-D. Böhmer1*

Institute of Molecular Cell Biology, Jena University Hospital, Jena,1 Department of Internal Medicine, Hematology, and Oncology, University of Münster, Münster, Germany2

Received 12 August 2004/ Returned for modification 14 September 2004/ Accepted 16 January 2005

Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTP{alpha} promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants.

* Corresponding author. Mailing address: Institute of Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, Drackendorfer Str. 1, D-07747 Jena, Germany. Phone: 49-3641-9325660. Fax: 49-3641-9325652. E-mail: i5frbo{at}rz.uni-jena.de.

Molecular and Cellular Biology, May 2005, p. 3690-3703, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3690-3703.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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