KAL1 binds FGFR1c

Stable Identifier
R-HSA-5654514
Type
Reaction [binding]
Species
Homo sapiens
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KAL1 is an extracellular matrix-associated protein that modulates signaling by FGFR1c. Mutations in the KAL1 gene are associated with Kallman syndrome, a genetic disorder characterized by olfactory bulb dysgenesis and hypogonadotrophic hypogonadism (Dode et al, 2003; Pitteloud et al, 2006; reviewed in Hu and Bouloux, 2010). KAL1 has been shown to interact with both FGFR1c and with heparan sulfate, with opposing effects on downstream signaling. Preformation of an FGFR1c:KAL1 complex inhibits the association of FGF ligand with the complex and subsequent receptor dimerization and in this way negatively regulates FGFR1c ligand-dependent signaling. In contrast, preformation of a KAL1:heparan sulfate complex promotes stable FGF ligand:receptor interaction thereby enhancing FGFR1c signal transduction (Hu et al, 2009; Hu et al, 2004; Soussi-Yanicostas et al, 1998).
KAL1 consists of an N-terminal cysteine rich domain, a whey acidic protein-like (WAP) domain, four fibronectin III (FnIII) repeats and a C-terminal histidine rich region. The N-terminal cysteine rich region, the WAP domain and the first FnIII domain contribute to the interaction with the D2 and D3 Ig-like domains of FGFR1c. D1 and the acid box of the receptor inhibit the interaction with KAL1 in a manner analogous to the inhibition of FGF binding (Hu et al, 2009). Consistent with this, missense mutations in D1 and the acid box that affect the interaction with KAL1 have been identified in patients with Kallmann syndrome (Dode and Hardelin, 2009). Similarly, loss-of function mutations in the FnIII domain of KAL1 that disrupt the interaction with FGFR1c have also been characterized (Hu et al, 2009; Robertson et al, 2001; Gonzalez-Martinez et al 2004; Oliviera et al, 2001).

Literature References
PubMed ID Title Journal Year
20117945 Novel insights in FGFR1 regulation: lessons from Kallmann syndrome

Hu, Y, Bouloux, PM

Trends Endocrinol. Metab. 2010
19696444 Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1

Hu, Y, Guimond, SE, Travers, P, Cadman, S, Hohenester, E, Turnbull, JE, Kim, SH, Bouloux, PM

J. Biol. Chem. 2009
15324302 Cross-talk of anosmin-1, the protein implicated in X-linked Kallmann's syndrome, with heparan sulphate and urokinase-type plasminogen activator

Hu, Y, González-Martínez, D, Kim, SH, Bouloux, PM

Biochem. J. 2004
18985070 Kallmann syndrome

Dodé, C, Hardelin, JP

Eur. J. Hum. Genet. 2009
15548653 Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism

González-Martínez, D, Kim, SH, Hu, Y, Guimond, S, Schofield, J, Winyard, P, Vannelli, GB, Turnbull, J, Bouloux, PM

J. Neurosci. 2004
12627230 Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

Dodé, C, Levilliers, J, Dupont, JM, De Paepe, A, Le Dû, N, Soussi-Yanicostas, N, Coimbra, RS, Delmaghani, S, Compain-Nouaille, S, Baverel, F, Pêcheux, C, Le Tessier, D, Cruaud, C, Delpech, M, Speleman, F, Vermeulen, S, Amalfitano, A, Bachelot, Y, Bouchard, P, Cabrol, S, Carel, JC, Delemarre-van de Waal, H, Goulet-Salmon, B, Kottler, ML, Richard, O, Sanchez-Franco, F, Saura, R, Young, J, Petit, C, Hardelin, JP

Nat. Genet. 2003
11463336 Molecular modelling and experimental studies of mutation and cell-adhesion sites in the fibronectin type III and whey acidic protein domains of human anosmin-1

Robertson, A, MacColl, GS, Nash, JA, Boehm, MK, Perkins, SJ, Bouloux, PM

Biochem. J. 2001
16764984 Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes

Pitteloud, N, Meysing, A, Quinton, R, Acierno, JS, Dwyer, AA, Plummer, L, Fliers, E, Boepple, P, Hayes, F, Seminara, S, Hughes, VA, Ma, J, Bouloux, P, Mohammadi, M, Crowley, WF

Mol. Cell. Endocrinol. 2006
11297579 The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics

Oliveira, LM, Seminara, SB, Beranova, M, Hayes, FJ, Valkenburgh, SB, Schipani, E, Costa, EM, Latronico, AC, Crowley, WF, Vallejo, M

J. Clin. Endocrinol. Metab. 2001
9730987 Anosmin-1 underlying the X chromosome-linked Kallmann syndrome is an adhesion molecule that can modulate neurite growth in a cell-type specific manner

Soussi-Yanicostas, N, Faivre-Sarrailh, C, Hardelin, JP, Levilliers, J, Rougon, G, Petit, C

J. Cell. Sci. 1998
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