SPRED1 (human, Q7Z699) curation notes

2026-10-01 initial review (claude-code)

Context: reviewed as a negative regulator of Ras-ERK signalling (Sprouty/SPRED feedback step for the ERK cascade module). Comparator: genes/human/SPRY4.

Mechanism: NF1 recruitment is the best-supported activity

• Neurofibromin is required for SPRED1 inhibition, and SPRED1 brings NF1 to the plasma membrane PMID:22751498 PMID:22751498
• Domain logic: EVH1 binds NF1, SPR domain targets the membrane PMID:22751498
• Acts at the level of Ras-GTP PMID:22751498
• Biochemistry: EVH1 binds the NF1 GRD GAPex region and does not change GAP activity PMID:27313208
• Structure of SPRED1 EVH1:NF1 GRD:KRAS PMID:32697994
• Legius mutations disrupt EVH1-GRD binding PMID:26635368
• Older RAF model (discovery paper, mouse) PMID:11493923 -- not supported by a direct RAF-binding/inhibition MF in later work; SPRED1 associates with B-RAF in the cytoplasm as a translocation step PMID:33872193
• Conclusion for the module: MF = GO:0043495 protein-membrane adaptor activity (NF1-to-membrane), not a kinase-inhibitor/RAF-binding MF (contrast SPRY4, whose core MF is GO:0004860 via RAF1). SPRED1 is the EVH1-containing paralog variant of the Sprouty feedback step.

Secondary activities

• TESK1 inhibition in vitro PMID:18216281
• DYRK1A modulation PMID:20736167
• KIT binding via KBD PMID:33872193
• S-acylated by ZDHHC17 PMID:24705354

Disease

• Legius syndrome PMID:17704776

Decisions

• 452 GO:0005515 rows: REMOVE (HT Y2H screens, HuRI, PP1 screens, ZDHHC17 substrate). NF1 row (PMID:26635368) MODIFY -> GO:0032794; PP1 row (PMID:19389623) MODIFY -> GO:0008157.
• No NOT annotations in GOA for SPRED1.
• UNDECIDED: nucleus (EXP PMID:16115197 abstract-only, abstract silent on nucleus; IEA SubCell mirror), and positive regulation of p53 DNA-damage signalling (ISS/IEA from mouse; cited PMID:20736167 abstract has no p53 content).
• GO:0060979 vasculogenesis involved in coronary vascular morphogenesis (IMP, PMID:23625462): MODIFY -> GO:2001213 negative regulation of vasculogenesis (knockdown enhances tube formation PMID:23625462).
• GO:0043408 regulation of MAPK cascade (TAS) MODIFY -> GO:0070373.
• NEW: GO:0043495 protein-membrane adaptor activity; GO:0046580 negative regulation of Ras protein signal transduction (comparators SPRY1/SPRY2/SPRY4 IBA and NF1 IEA carry it; SPRED1 is in separate PANTHER family PTHR11202).
• Deep research (falcon) agrees: [file:human/SPRED1/SPRED1-deep-research-falcon.md "SPRED1 therefore has no catalytic reaction, enzyme substrate specificity or transport substrate of its own."]