Son of sevenless homolog 1 is a
protein that in humans is encoded by the SOS1gene.[5][6]
Function
SOS1 is a
guanine nucleotide exchange factor (GEF) which interacts with
Ras proteins to phosphorylate GDP into GTP, or from an inactive state to an active state to signal cell proliferation. RAS genes (e.g., MIM 190020) encode membrane-bound guanine nucleotide-binding proteins that function in the transduction of signals that control cell growth and differentiation. Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins. GTP binding can be catalyzed by
guanine nucleotide exchange factors for RAS, and GTP hydrolysis can be accelerated by
GTPase-activating proteins (GAPs). The first exchange factor to be identified for RAS was the S. cerevisiae Cdc25 gene product (not to be confused with the S. pombeCdc25). Genetic analysis indicated that CDC25 is essential for activation of RAS proteins. In Drosophila, the protein encoded by the 'son of sevenless' gene (Sos) contains a domain that shows sequence similarity with the catalytic domain of Cdc25. Sos may act as a positive regulator of RAS by promoting guanine nucleotide exchange.[7]
Clinical significance
Recent studies also show that mutations in Sos1 can cause
Noonan syndrome[8] and hereditary gingival fibromatosis type 1.[9] Noonan syndrome has also been shown to be caused by mutations in
KRAS and
PTPN11 genes.[10] activators of the MAP kinase pathway.
Inhibitors and activators
In 2019, the first SOS1 inhibitor, BAY-293,[11] was published which met the quality criteria for a 'Donated Chemical Probe' as defined by the
Structural Genomics Consortium.[12] Shortly after, the discovery of BI-3406[13][14] was published.
In 2018, Fesik et al. reported the discovery of benzimidazole-derived SOS1 activators[15] (e.g. VUBI1).
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Webb GC, Jenkins NA, Largaespada DA, Copeland NG, Fernandez CS, Bowtell DD (October 1993). "Mammalian homologues of the Drosophila Son of sevenless gene map to murine chromosomes 17 and 12 and to human chromosomes 2 and 14, respectively". Genomics. 18 (1): 14–19.
doi:
10.1006/geno.1993.1421.
PMID8276400.
^Xiao S, Wang X, Qu B, Yang M, Liu G, Bu L, et al. (September 2000). "Refinement of the locus for autosomal dominant hereditary gingival fibromatosis (GINGF) to a 3.8-cM region on 2p21". Genomics. 68 (3): 247–252.
doi:
10.1006/geno.2000.6285.
PMID10995566.
^
abcChin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O (October 1997). "Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells". Biochemical and Biophysical Research Communications. 239 (2): 412–417.
doi:
10.1006/bbrc.1997.7480.
PMID9344843.
^
abPandey P, Kharbanda S, Kufe D (September 1995). "Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein". Cancer Research. 55 (18): 4000–4003.
PMID7664271.
^Blagoev B, Kratchmarova I, Ong SE, Nielsen M, Foster LJ, Mann M (March 2003). "A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling". Nature Biotechnology. 21 (3): 315–318.
doi:
10.1038/nbt790.
PMID12577067.
S2CID26838266.
^Wunderlich L, Faragó A, Buday L (January 1999). "Characterization of interactions of Nck with Sos and dynamin". Cellular Signalling. 11 (1): 25–29.
doi:
10.1016/s0898-6568(98)00027-8.
PMID10206341.
^Kim MJ, Chang JS, Park SK, Hwang JI, Ryu SH, Suh PG (July 2000). "Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-gamma1". Biochemistry. 39 (29): 8674–8682.
doi:
10.1021/bi992558t.
PMID10913276.
Pandey P, Kharbanda S, Kufe D (September 1995). "Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein". Cancer Research. 55 (18): 4000–4003.
PMID7664271.
Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, et al. (May 1993). "Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling". Nature. 363 (6424): 85–88.
Bibcode:
1993Natur.363...85L.
doi:
10.1038/363085a0.
PMID8479541.
S2CID4323174.
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D (May 1993). "Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2". Science. 260 (5112): 1338–1343.
Bibcode:
1993Sci...260.1338C.
doi:
10.1126/science.8493579.
PMID8493579.
Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O (October 1997). "Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells". Biochemical and Biophysical Research Communications. 239 (2): 412–417.
doi:
10.1006/bbrc.1997.7480.
PMID9344843.
Curto M, Frankel P, Carrero A, Foster DA (February 1998). "Novel recruitment of Shc, Grb2, and Sos by fibroblast growth factor receptor-1 in v-Src-transformed cells". Biochemical and Biophysical Research Communications. 243 (2): 555–560.
doi:
10.1006/bbrc.1997.7982.
PMID9480847.
Son of sevenless homolog 1 is a
protein that in humans is encoded by the SOS1gene.[5][6]
Function
SOS1 is a
guanine nucleotide exchange factor (GEF) which interacts with
Ras proteins to phosphorylate GDP into GTP, or from an inactive state to an active state to signal cell proliferation. RAS genes (e.g., MIM 190020) encode membrane-bound guanine nucleotide-binding proteins that function in the transduction of signals that control cell growth and differentiation. Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins. GTP binding can be catalyzed by
guanine nucleotide exchange factors for RAS, and GTP hydrolysis can be accelerated by
GTPase-activating proteins (GAPs). The first exchange factor to be identified for RAS was the S. cerevisiae Cdc25 gene product (not to be confused with the S. pombeCdc25). Genetic analysis indicated that CDC25 is essential for activation of RAS proteins. In Drosophila, the protein encoded by the 'son of sevenless' gene (Sos) contains a domain that shows sequence similarity with the catalytic domain of Cdc25. Sos may act as a positive regulator of RAS by promoting guanine nucleotide exchange.[7]
Clinical significance
Recent studies also show that mutations in Sos1 can cause
Noonan syndrome[8] and hereditary gingival fibromatosis type 1.[9] Noonan syndrome has also been shown to be caused by mutations in
KRAS and
PTPN11 genes.[10] activators of the MAP kinase pathway.
Inhibitors and activators
In 2019, the first SOS1 inhibitor, BAY-293,[11] was published which met the quality criteria for a 'Donated Chemical Probe' as defined by the
Structural Genomics Consortium.[12] Shortly after, the discovery of BI-3406[13][14] was published.
In 2018, Fesik et al. reported the discovery of benzimidazole-derived SOS1 activators[15] (e.g. VUBI1).
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Webb GC, Jenkins NA, Largaespada DA, Copeland NG, Fernandez CS, Bowtell DD (October 1993). "Mammalian homologues of the Drosophila Son of sevenless gene map to murine chromosomes 17 and 12 and to human chromosomes 2 and 14, respectively". Genomics. 18 (1): 14–19.
doi:
10.1006/geno.1993.1421.
PMID8276400.
^Xiao S, Wang X, Qu B, Yang M, Liu G, Bu L, et al. (September 2000). "Refinement of the locus for autosomal dominant hereditary gingival fibromatosis (GINGF) to a 3.8-cM region on 2p21". Genomics. 68 (3): 247–252.
doi:
10.1006/geno.2000.6285.
PMID10995566.
^
abcChin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O (October 1997). "Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells". Biochemical and Biophysical Research Communications. 239 (2): 412–417.
doi:
10.1006/bbrc.1997.7480.
PMID9344843.
^
abPandey P, Kharbanda S, Kufe D (September 1995). "Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein". Cancer Research. 55 (18): 4000–4003.
PMID7664271.
^Blagoev B, Kratchmarova I, Ong SE, Nielsen M, Foster LJ, Mann M (March 2003). "A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling". Nature Biotechnology. 21 (3): 315–318.
doi:
10.1038/nbt790.
PMID12577067.
S2CID26838266.
^Wunderlich L, Faragó A, Buday L (January 1999). "Characterization of interactions of Nck with Sos and dynamin". Cellular Signalling. 11 (1): 25–29.
doi:
10.1016/s0898-6568(98)00027-8.
PMID10206341.
^Kim MJ, Chang JS, Park SK, Hwang JI, Ryu SH, Suh PG (July 2000). "Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-gamma1". Biochemistry. 39 (29): 8674–8682.
doi:
10.1021/bi992558t.
PMID10913276.
Pandey P, Kharbanda S, Kufe D (September 1995). "Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein". Cancer Research. 55 (18): 4000–4003.
PMID7664271.
Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, et al. (May 1993). "Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling". Nature. 363 (6424): 85–88.
Bibcode:
1993Natur.363...85L.
doi:
10.1038/363085a0.
PMID8479541.
S2CID4323174.
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D (May 1993). "Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2". Science. 260 (5112): 1338–1343.
Bibcode:
1993Sci...260.1338C.
doi:
10.1126/science.8493579.
PMID8493579.
Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O (October 1997). "Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells". Biochemical and Biophysical Research Communications. 239 (2): 412–417.
doi:
10.1006/bbrc.1997.7480.
PMID9344843.
Curto M, Frankel P, Carrero A, Foster DA (February 1998). "Novel recruitment of Shc, Grb2, and Sos by fibroblast growth factor receptor-1 in v-Src-transformed cells". Biochemical and Biophysical Research Communications. 243 (2): 555–560.
doi:
10.1006/bbrc.1997.7982.
PMID9480847.