SPRED2 Gene: Function, Mutations, and Associated Diseases | NCBI, UniProt, ClinVar

SPRED2 (Sprouty-related EVH1 domain-containing protein 2) is a protein-coding gene located on chromosome 2p14. It encodes a member of the Sprouty/SPRED family of proteins that function as negative regulators of the RAS-MAPK signaling pathway. SPRED2 inhibits the activation of ERK by interacting with Ras and Raf, thereby modulating cell proliferation, differentiation, and migration. Loss-of-function mutations in SPRED2 are associated with Noonan syndrome and a neurofibromatosis type 1-like phenotype. The gene is also implicated in tumor suppression, with somatic mutations and reduced expression observed in various cancers, including melanoma, lung cancer, and leukemia.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• RAS-MAPK signaling pathway (KEGG: hsa04010)

• Signaling by Receptor Tyrosine Kinases (Reactome: R-HSA-9006934)

• Negative regulation of MAPK pathway (Reactome: R-HSA-5675220)

• Signaling by RAS mutants (Reactome: R-HSA-6802949)

SPRED2 is a 418-amino acid protein containing an N-terminal EVH1 domain and a C-terminal Sprouty-related domain. It localizes to the cytoplasm and plasma membrane, where it binds to Ras and Raf, preventing ERK phosphorylation. SPRED2 acts as a tumor suppressor by restraining mitogenic signaling. Its expression is regulated by transcription factors such as ETS1 and is frequently silenced in cancers via promoter methylation or mutation. The protein also interacts with other signaling molecules, including c-Kit and FLT3, modulating hematopoietic cell growth.