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Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway.
Mol Cell Biol. 2007 Oct; 27(19):6903-12.MC

Abstract

Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by abnormalities in lacrimal and salivary glands, in teeth, and in the distal limbs. Genetic studies have implicated heterozygous mutations in fibroblast growth factor 10 (FGF10) and in FGF receptor 2 (FGFR2) in LADD syndrome. However, it is not clear whether LADD syndrome mutations (LADD mutations) are gain- or loss-of-function mutations. In order to reveal the molecular mechanism underlying LADD syndrome, we have compared the biological properties of FGF10 LADD and FGFR2 LADD mutants to the activities of their normal counterparts. These experiments show that the biological activities of three different FGF10 LADD mutants are severely impaired by different mechanisms. Moreover, haploinsufficiency caused by defective FGF10 mutants leads to LADD syndrome. We also demonstrate that the tyrosine kinase activities of FGFR2 LADD mutants expressed in transfected cells are strongly compromised. Since tyrosine kinase activity is stimulated by ligand-induced receptor dimerization, FGFR2 LADD mutants may also exert a dominant inhibitory effect on signaling via wild-type FGFR2 expressed in the same cell. These experiments underscore the importance of signal strength in mediating biological responses and that relatively small changes in receptor signaling may influence the outcome of developmental processes in cells or organs that do not possess redundant signaling pathway.

Authors+Show Affiliations

Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17682060

Citation

Shams, Imad, et al. "Lacrimo-auriculo-dento-digital Syndrome Is Caused By Reduced Activity of the Fibroblast Growth Factor 10 (FGF10)-FGF Receptor 2 Signaling Pathway." Molecular and Cellular Biology, vol. 27, no. 19, 2007, pp. 6903-12.
Shams I, Rohmann E, Eswarakumar VP, et al. Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway. Mol Cell Biol. 2007;27(19):6903-12.
Shams, I., Rohmann, E., Eswarakumar, V. P., Lew, E. D., Yuzawa, S., Wollnik, B., Schlessinger, J., & Lax, I. (2007). Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway. Molecular and Cellular Biology, 27(19), 6903-12.
Shams I, et al. Lacrimo-auriculo-dento-digital Syndrome Is Caused By Reduced Activity of the Fibroblast Growth Factor 10 (FGF10)-FGF Receptor 2 Signaling Pathway. Mol Cell Biol. 2007;27(19):6903-12. PubMed PMID: 17682060.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway. AU - Shams,Imad, AU - Rohmann,Edyta, AU - Eswarakumar,Veraragavan P, AU - Lew,Erin D, AU - Yuzawa,Satoru, AU - Wollnik,Bernd, AU - Schlessinger,Joseph, AU - Lax,Irit, Y1 - 2007/08/06/ PY - 2007/8/8/pubmed PY - 2008/1/23/medline PY - 2007/8/8/entrez SP - 6903 EP - 12 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 27 IS - 19 N2 - Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by abnormalities in lacrimal and salivary glands, in teeth, and in the distal limbs. Genetic studies have implicated heterozygous mutations in fibroblast growth factor 10 (FGF10) and in FGF receptor 2 (FGFR2) in LADD syndrome. However, it is not clear whether LADD syndrome mutations (LADD mutations) are gain- or loss-of-function mutations. In order to reveal the molecular mechanism underlying LADD syndrome, we have compared the biological properties of FGF10 LADD and FGFR2 LADD mutants to the activities of their normal counterparts. These experiments show that the biological activities of three different FGF10 LADD mutants are severely impaired by different mechanisms. Moreover, haploinsufficiency caused by defective FGF10 mutants leads to LADD syndrome. We also demonstrate that the tyrosine kinase activities of FGFR2 LADD mutants expressed in transfected cells are strongly compromised. Since tyrosine kinase activity is stimulated by ligand-induced receptor dimerization, FGFR2 LADD mutants may also exert a dominant inhibitory effect on signaling via wild-type FGFR2 expressed in the same cell. These experiments underscore the importance of signal strength in mediating biological responses and that relatively small changes in receptor signaling may influence the outcome of developmental processes in cells or organs that do not possess redundant signaling pathway. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/17682060/Lacrimo_auriculo_dento_digital_syndrome_is_caused_by_reduced_activity_of_the_fibroblast_growth_factor_10__FGF10__FGF_receptor_2_signaling_pathway_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=17682060 DB - PRIME DP - Unbound Medicine ER -