The SPRE (also known as SPRED) proteins have the following domains: an N-terminal EVH1 domain, a unique KBD (c-Kit kinase binding) domain which is phosphorylated by the stem cell factor receptor c-Kit, and a C-terminal cysteine-rich SPR (Sprouty-related) domain which is involved in membrane localization. This entry represents the EVH1 domain of SPRE. Proteins containing this domaininclude Spred1 which interacts with both Ras and Raf through its SPR domain; Spred2 which is the most abundant isoform; and Spred3 which has a non-functional KBD and maintains the inhibitory action on Raf. Legius syndrome is caused by heterozygous mutations in Spred1. Both EVH1 and SPR domains are involved in the inhibition of the MAP kinase pathway by SPRE proteins. The specific function of the EVH1 domain is unknown and there are no known interacting proteins to date. EVH1 has a PH-like fold, despite having minimal sequence similarity to PH or PTB domains [, , ].
Sprouty (Spry) and Spred (Sprouty related EVH1 domain) proteins have been identified as inhibitors of the Ras/mitogen-activated protein kinase(MAPK) cascade, a pathway crucial for developmental processes initiated by activation of various receptor tyrosine kinases [, ]. These proteins share a conserved, C-terminal cysteine-rich region, the SPR domain. This domain has been defined as a novel cytosol to membrane translocation domain [, , , ]. It has been found to be a PtdIns(4,5)P2-binding domain that targets the proteins to a cellular localization that maximizes their inhibitory potential [, ]. It also mediates homodimer formation of these proteins [, ].The SPR domain can occur in association with the WH1 domain (see ) (located in the N-terminal part of the proteins) in the Spred proteins.
