Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia

Cho, Jay Y.; Guo, Changsheng; Torello, Monica; Lunstrum, Gregory P.; Iwata, Tomoko; Deng, Chu‐Xia; Horton, William A.

doi:10.1073/pnas.2237184100

Cited by 106 publications

(106 citation statements)

References 51 publications

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“…We have reported previously that activated FGFR3 is degraded in lysosomes and is directed into this pathway by c-Cbl-mediated ubiquitination (19). In fact, we observed that FGFR3 bearing gain-of-function mutations progress through this pathway less efficiently than WT-FGFR3.…”

Section: Discussionmentioning

confidence: 62%

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Fibroblast Growth Factor Receptor 3 (FGFR3) Is a Strong Heat Shock Protein 90 (Hsp90) Client

Laederich

Degnin

Lunstrum

et al. 2011

Journal of Biological Chemistry

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Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of growth and differentiation, whose aberrant activation causes a number of genetic diseases including achondroplasia and cancer. Hsp90 is a specialized molecular chaperone involved in stabilizing a select set of proteins termed clients. Here, we delineate the relationship of Hsp90 and co-chaperone Cdc37 with FGFR3 and the FGFR family. FGFR3 strongly associates with these chaperone complexes and depends on them for stability and function. Inhibition of Hsp90 function using the geldanamycin analog 17-AAG induces the ubiquitination and degradation of FGFR3 and reduces the signaling capacity of FGFR3. Other FGFRs weakly interact with these chaperones and are differentially influenced by Hsp90 inhibition. The Hsp90-related ubiquitin ligase CHIP is able to interact and destabilize FGFR3. Our results establish FGFR3 as a strong Hsp90 client and suggest that modulating Hsp90 chaperone complexes may beneficially influence the stability and function of FGFR3 in disease.Fibroblast growth factor receptors (FGFRs) 3 are responsible for coordinating numerous developmental and cellular processes such as cellular differentiation and growth (1). Germ line and somatic mutations in FGFRs give rise to genetic disorders of skeletal development and cancer (2, 3), which reflect increased or misregulated FGFR signals. FGFR3 is mutated or abnormally expressed in the most common form of human dwarfism, achondroplasia, and cancers, notably in superficial bladder cancer and multiple myeloma (4, 5). Interestingly, identical mutations are found in bone growth disorders and cancer, suggesting that they share common pathogenetic features and may respond to similar therapeutic approaches (6).Hsp90 is a molecular chaperone that is abundantly and ubiquitously expressed within cells (7,8). It is involved in initial protein folding as well as in stabilizing proteins with unstable domains. For kinases, the dedicated co-chaperone Cdc37 helps recruit and control Hsp90 association with the folding complex. Some kinases depend on Hsp90 constitutively for their stability; these "strong clients" include ErbB2 and AKT (9, 10). Others require Hsp90 only when rendered constitutively active by mutation, i.e. 12). Inhibition of Hsp90 function using small molecule inhibitors alters chaperone complex composition and promotes the association of E3-ubiquitin ligases such as CHIP (carboxyl terminus of Hsp70-interacting protein), leading to client ubiquitination and degradation (13).Many Hsp90-stabilized kinases are oncogenic, which has led to the development of Hsp90 inhibitors for cancer therapy. Indeed, geldanamycin derivatives such as 17-AAG and other Hsp90 inhibitors have progressed to phase II clinical trials (14). Hsp90 inhibitors have also been investigated in preclinical models of genetic diseases of mutated Hsp90 clients such as the androgen receptor in spinal and bulbar muscular atrophy (Kennedy disease) (15, 16).Here, we define the relationship of FGFR3 and the FGFR family with Hsp90 and i...

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Section: Discussionmentioning

confidence: 62%

“…The generation of the COS7 stable cell lines has been previously described (19). Because the effective dose of 17-AAG (InvivoGen) is affected by cell number (20), all HEK 293-based cell lines were plated at 2 ϫ 10 5 cells/cm 2 , and RT112 cells were plated at 2.4 ϫ 10 5 cells/cm 2 .…”

Section: Methodsmentioning

confidence: 99%

Fibroblast Growth Factor Receptor 3 (FGFR3) Is a Strong Heat Shock Protein 90 (Hsp90) Client

Laederich

Degnin

Lunstrum

et al. 2011

Journal of Biological Chemistry

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“…A further dramatic consequence related to SADDAN (and TDII) mutants is that they fail to be turned over. Accordingly, a defect in receptor degradation has been recently described for the achondroplasia mutation (24). Because the du- ration of signaling could be critical for a cellular response, failure in the mechanisms that attenuate receptor signaling or down-regulate receptor transcription (25) may have devastating effects, thus justifying the severity of the diseases.…”

Section: Discussionmentioning

confidence: 99%

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

Lievens

Mutinelli

Baynes

et al. 2004

Journal of Biological Chemistry

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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.Protein tyrosine kinase receptors play a fundamental role in the control of a variety of cellular processes during embryonic development; furthermore, they regulate many metabolic and physiological processes in a variety of tissues and organs (1-3). Indeed, aberrant receptor kinase activation results in severe diseases such as cancer, diabetes, cardiovascular diseases, and many others (4). Fibroblast growth factor receptors (FGFRs) 1 belong to the tyrosine kinase receptor (RTK) family. FGFRs are glycosylated transmembrane proteins that, upon binding with fibroblast growth factor ligands and heparin, dimerize and undergo interchain autophosphorylation of key tyrosine residues, thus transmitting signals into the cells (5-8). Tyrosine autophosphorylation sites in the cytoplasmic domain of the receptor serve as docking sites for the Src homology 2 domain of signaling proteins that are recruited and activated upon growth factor stimulation (9). FGFR3 is a member of the FGFR family and plays a pivotal role in skeletal development as a negative regulator of bone growth, because targeted disruption of the mouse FGFR3 gene causes a skeletal overgrowth (10, 11). In addition, mutations in FGFR3 are frequently involved in a variety of human skeletal disorders and cancer (12, 13).Particular attention has been paid to the Lys-650 codon of FGFR3 located within a critical regi...

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“…Interestingly, some of the oncogenic FGFR mutants have been shown to be inefficiently degraded. For example, the constitutively active mutants of FGFR3, K650E and G380R, which are found in bladder, prostate, and testicle cancer, and MM, as well as in skeletal disorders (Table 1), were shown to escape into a recycling pathway, where they accumulated as active receptors with a half-life of about twice that of wild-type FGFR3 (149). Thus, defective endocytosis contributes to the gain of function of these FGFR3 mutants.…”

Section: Impaired Termination Of Fgfr Signalingmentioning

confidence: 99%

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

Haugsten

Wiedlocha

Olsnes

et al. 2010

Molecular Cancer Research

278

226

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The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression.

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Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia

Cited by 106 publications

References 51 publications

Fibroblast Growth Factor Receptor 3 (FGFR3) Is a Strong Heat Shock Protein 90 (Hsp90) Client

Fibroblast Growth Factor Receptor 3 (FGFR3) Is a Strong Heat Shock Protein 90 (Hsp90) Client

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

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

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