Reactome | SPRED dimer binds NF1

SPRED dimer binds NF1

Stable Identifier

R-HSA-5658438

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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Sprouty-related proteins (SPRED) 1, 2 and 3 are negative regulators of the MAPK pathway that act at least in part by recruiting the RAS GAP protein neurofibromin 1 (NF1) to the plasma membrane (Kato et al, 2003; King et al, 2006; Stowe et al, 2012). NF1, a negative regulator of RAS is a tumor suppressor that is mutated in the familial cancer syndrome neurofibromatosis I as well as in sporadic cases of glioblastoma, non-small cell lung cancers, neuroblastoma and melanoma (Martin et al, 1990; Bollag et al, 1996; reviewed in Bollag and McCormick, 1992; Maertens and Cichowski, 2014).

Plasma membrane-association of the SPRED proteins themselves depends on the C-terminal SPR domain. Mutations in this region abrogate membrane localization of the protein (King et al, 2005; Stowe et al, 2012). Membrane association may also be promoted by interaction of the SPRED proteins with RAS (Wakioka et al, 2001). Interaction with NF1 is mediated by the SPRED EVH1 domain, and mutations in this region affect both NF1 recruitment and the ability of SPRED and NF1 proteins to negatively regulate RAS pathway activity (Stowe et al, 2012; reviewed in McClatchey and Cichowski, 2012).

Literature References

PubMed ID	Title	Journal	Year
11493923	Spred is a Sprouty-related suppressor of Ras signalling Wakioka, T, Sasaki, A, Kato, R, Shouda, T, Matsumoto, A, Miyoshi, K, Tsuneoka, M, Komiya, S, Baron, R, Yoshimura, A	Nature	2001
8563751	Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells Bollag, G, Clapp, DW, Shih, S, Adler, F, Zhang, YY, Thompson, P, Lange, BJ, Freedman, MH, McCormick, F, Jacks, T, Shannon, K	Nat. Genet.	1996
2121370	The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21 Martin, GA, Viskochil, D, Bollag, G, McCabe, PC, Crosier, WJ, Haubruck, H, Conroy, L, Clark, R, O'Connell, P, Cawthon, RM, Innis, M A, McCormick, F	Cell	1990
16478641	Eve-3: a liver enriched suppressor of Ras/MAPK signaling King, JA, Corcoran, NM, D'Abaco, GM, Straffon, AF, Smith, CT, Poon, CL, Buchert, M, I, S, Hall, NE, Lock, P, Hovens, CM	J. Hepatol.	2006
12646235	Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation Kato, R, Nonami, A, Taketomi, T, Wakioka, T, Kuroiwa, A, Matsuda, Y, Yoshimura, A	Biochem. Biophys. Res. Commun.	2003
22751498	A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1 Stowe, IB, Mercado, EL, Stowe, TR, Bell, EL, Oses-Prieto, JA, Hernández, H, Burlingame, AL, McCormick, F	Genes Dev.	2012
24814062	An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer Maertens, O, Cichowski, K	Adv Biol Regul	2014
1570011	Ras regulation. NF is enough of GAP Bollag, G, McCormick, F	Nature	1992
22802525	SPRED proteins provide a NF-ty link to Ras suppression McClatchey, AI, Cichowski, K	Genes Dev.	2012
15683364	Distinct requirements for the Sprouty domain for functional activity of Spred proteins King, JA, Straffon, AF, D'Abaco, GM, Poon, CL, I, ST, Smith, CM, Buchert, M, Corcoran, NM, Hall, NE, Callus, BA, Sarcevic, B, Martin, D, Lock, P, Hovens, CM	Biochem. J.	2005