SPRED dimer binds NF1

Stable Identifier
R-HSA-5658438
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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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
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
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
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
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