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

J. Biol. Chem., Vol. 279, Issue 41, 43254-43260, October 8, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/41/43254    most recent M405247200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Lievens, P. M.-J. Articles by Liboi, E. Search for Related Content PubMed PubMed Citation Articles by Lievens, P. M.-J. Articles by Liboi, E. Social Bookmarking                      What's this?

The Kinase Activity of Fibroblast Growth Factor Receptor 3 with Activation Loop Mutations Affects Receptor Trafficking and Signaling^*

Patricia M.-J. Lievens, Chiara Mutinelli, Darcie Baynes, and Elio Liboi

From the Division of Biochemistry, Department of Neurological Sciences, University of Verona Medical School, 37134 Verona, Italy

Amino acid substitutions at the Lys-650 codon within the activation loop kinase domain of fibroblast growth factor receptor 3 (FGFR3) result in graded constitutive phosphorylation of the receptor. Accordingly, the Lys-650 mutants are associated with dwarfisms with graded clinical severity. To assess the importance of the phosphorylation level on FGFR3 maturation along the secretory pathway, hemagglutinin A-tagged derivatives were studied. The highly activated SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) mutant accumulates in its immature and phosphorylated form in the endoplasmic reticulum (ER), which fails to be degraded. Furthermore, the Janus kinase (Jak)/STAT pathway is activated from the ER by direct recruitment of Jak1. Abolishing the autocatalytic property of the mutated FGFR3 by replacing the critical Tyr-718 reestablishes the receptor full maturation and inhibits signaling. Differently, the low activated hypochondroplasia mutant is present as a mature phosphorylated form on the plasma membrane, although with a delayed transition in the ER, and is completely processed. Signaling does not occur in the presence of brefeldin A; instead, STAT1 is activated when protein secretion is blocked with monensin, suggesting that the hypochondroplasia receptor signals at the exit from the ER. Our results suggest that kinase activity affects FGFR3 trafficking and determines the spatial segregation of signaling pathways. Consequently, the defect in down-regulation of the highly activated receptors results in the increased signaling capacity from the intracellular compartments, and this may determine the severity of the diseases.

Received for publication, May 11, 2004 , and in revised form, June 30, 2004.

^* This investigation was supported by Telethon Grant GP0164Y01, NATO Collaborative Linkage Grant 977848 (to E. L.), the Italian Association for Studies on Achondroplasia (AISAc), and an Italian Ministry of Education COFIN 2003 grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 011-39-0458027666; Fax: 011-39-0458027170; E-mail: Elio.liboi{at}univr.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. M. Haugsten, J. Malecki, S. M. S. Bjorklund, S. Olsnes, and J. Wesche Ubiquitination of Fibroblast Growth Factor Receptor 1 Is Required for Its Intracellular Sorting but Not for Its Endocytosis Mol. Biol. Cell, August 1, 2008; 19(8): 3390 - 3403. [Abstract] [Full Text] [PDF]

				J. Chen, I. R. Williams, B. H. Lee, N. Duclos, B. J. P. Huntly, D. J. Donoghue, and D. G. Gilliland Constitutively activated FGFR3 mutants signal through PLC{gamma}-dependent and -independent pathways for hematopoietic transformation Blood, July 1, 2005; 106(1): 328 - 337. [Abstract] [Full Text] [PDF]

				N. Nowroozi, S. Raffioni, T. Wang, B. L. Apostol, R. A. Bradshaw, and L. M. Thompson Sustained ERK1/2 but not STAT1 or 3 activation is required for thanatophoric dysplasia phenotypes in PC12 cells Hum. Mol. Genet., June 1, 2005; 14(11): 1529 - 1538. [Abstract] [Full Text] [PDF]

				D.-E. Schmidt-Arras, A. Bohmer, B. Markova, C. Choudhary, H. Serve, and F.-D. Bohmer Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases Mol. Cell. Biol., May 1, 2005; 25(9): 3690 - 3703. [Abstract] [Full Text] [PDF]