KAL1 is an extracellular matrix-associated protein that modu...

created [InstanceEdit:5654374] Rothfels, Karen, 2014-12-03
dbId 5654373
displayName KAL1 is an extracellular matrix-associated protein that modu...
modified [InstanceEdit:8851416] Rothfels, Karen, 2016-01-06
schemaClass Summation
text 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).
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