Sprouty-related EVH1 domain-containing protein 1 (SPRED1) (SPRED1)

Sprouty-related EVH1 domain-containing protein 1 (SPRED1) is a key negative regulator of the RAS/MAPK signaling pathway, acting as a scaffold that recruits the RasGAP protein Neurofibromin (NF1) to the plasma membrane to inactivate RAS [2, 16]. By inhibiting the transition of RAS from its active GTP-bound state to its inactive GDP-bound state, SPRED1 suppresses downstream signaling that drives cell growth, differentiation, and survival [1, 2]. Germline mutations in SPRED1 lead to Legius syndrome, a condition characterized by café-au-lait spots and cognitive impairments, while somatic loss or downregulation of SPRED1 is a hallmark of several cancers, including melanoma and acute myeloid leukemia [1, 4, 8]. In these oncogenic contexts, the absence of SPRED1 results in hyperactive MAPK signaling and contributes to resistance against BRAF and MEK inhibitors [14]. Therapeutic strategies targeting SPRED1 focus on restoring its expression through epigenetic modifiers like DNA methyltransferase inhibitors or utilizing RNA-based approaches, such as mRNA delivery or microRNA inhibitors (e.g., targeting miR-126), to bypass endogenous suppression and reinstate pathway control [3, 13, 18].

Other names

SPRED-1hSpred1NFLSPPP1R147EVH1/Sprouty domain containing proteinSuppressor of Ras/MAPK activation

SPRED1 recruits Neurofibromin (NF1) to the plasma membrane to act as a RasGAP, thereby inhibiting RAS/MAPK signaling; drugs like 5-Azacytidine upregulate SPRED1 mRNA via promoter demethylation.