title: SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling.
abstract: The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is tightly controlled by negative feedback regulators, such as the tumor suppressor SPRED1. The SPRED1 gene also carries loss-of-function mutations in the RASopathy Legius syndrome. Growth factor stimulation translocates SPRED1 to the plasma membrane, triggering its inhibitory activity. However, it remains unclear whether SPRED1 there acts at the level of Ras or Raf. We show that pharmacological or galectin-1 (Gal-1)-mediated induction of B- and C-Raf-containing dimers translocates SPRED1 to the plasma membrane. This is facilitated in particular by SPRED1 interaction with B-Raf and, via its N terminus, with Gal-1. The physiological significance of these novel interactions is supported by two Legius syndrome-associated mutations that show diminished binding to both Gal-1 and B-Raf. On the plasma membrane, SPRED1 becomes enriched in acidic membrane domains to specifically perturb membrane organization and extracellular signal-regulated kinase (ERK) signaling of active K-ras4B (here, K-ras) but not H-ras. However, SPRED1 also blocks on the nanoscale the positive effects of Gal-1 on H-ras. Therefore, a combinatorial expression of SPRED1 and Gal-1 potentially regulates specific patterns of K-ras- and H-ras-dependent signaling output. More broadly, our results open up the possibility that related SPRED and Sprouty proteins act in a similar Ras and Raf isoform-specific manner.
authors: Turku Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors: Elina
authors: E
authors: Siljamäki
authors: Turku Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland daniel.abankwa@btk.fi.
authors: Daniel
authors: 0000-0003-2769-0745
authors: D
authors: Abankwa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D019080:Cafe-au-Lait Spots / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D037483:Galectin 1 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D037483:Galectin 1; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; C445499:LGALS1 protein, human; D008565:Membrane Proteins; C504812:SPRED1 protein, human; D004815:Epidermal Growth Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)