SOS1 is presumed to be recruited to FLT3 receptors through interaction with GRB2, as is the case for the wild-type receptor (reviewed in Kazi and Ronnstrand, 2019). SOS is a nucleotide exchange factor for RAS and activates signaling through the RAS-RAF-MAPK pathway downstream of oncogenic FLT3 mutants (Zhang et al, 1999; Mizuki et al, 2000; Hayakawa et al, 2000; Voisset et al, 2010; Arora et al, 2011; reviewed in Kazi and Ronnstrand, 2019).

RAS guanyl nucleotide exchange factor SOS1 recruited to MET receptor through association with RANBP9 catalyzes guanyl nucleotide exchange on RAS from GDP to GTP, resulting in RAS activation (Wang et al. 2002).

Sos1 bound to exogenously expressed human GRB2 in complex with phosphorylated rat oncoprotein Erbb2mut catalyzes endogenous Ras guanyl--nucleotide exchange in mouse fibroblasts.

SOS1 (SOS) is stably bound to GRB2, which transiently associates with phosphorylated CSF1R. In response to the activation of CSF1R by CSF1, SOS1 promotes RAS to exchange of GDP for GTP (inferred from mouse homologs) and thereby activates the RAS-RAF-MEK-ERK1,2 signaling pathway. Myeloid cells contain the KRAS isoform of RAS. KRAS:GTP enhances proliferation of macrophages (inferred from mouse homologs).
GRB2 has been shown to bind phosphotyrosine-699 of CSF1R (phosphotyrosine-697 of mouse Csf1r), however phosphorylation of tyrosines 544, 559, and 807 of mouse Csf1r are together sufficient for the full proliferative response mediated via the RS-RAF-MEK-ERK1,2 pathway (Yu et al. 2012) and mouse Csf1r lacking phosophotyrosine-697 can still activate ERK (Lee and States 2000), Csf1r phosphotyrosine-697 (human CSF1R phosphotyrosine-699) is likely not the only GRB2:SOS binding site

SOS1 in complex with GRB2 and p-Y349,350-SHC1:p-ERBB4 activates RAS by mediating guanyl nucleotide exchange, which results in the activation of RAF/MAP kinase cascade (Kainulainen et al. 2000).

Activated MET receptor recruits the RAS guanyl nucleotide exchange factor (GEF) SOS1 indirectly, either through the GRB2 adapter (Ponzetto et al. 1994, Fournier et al. 1996, Shen and Novak 1997, Besser et al. 1997), GAB1 (Weidner et al. 1996) or SHC1 and GRB2 (Pelicci et al. 1995), or RANBP9 (Wang et al. 2002, Wang et al. 2004). Association of SOS1 with the activated MET receptor complex leads to exchange of GDP to GTP on RAS and activation of RAS signaling (Pelicci et al. 1995, Besser et al. 1997, Shen and Novak 1997, Wang et al. 2004).
PTPN11 (SHP2) may contribute to activation of RAS signaling downstream of MET (Schaeper et al. 2000, Furcht et al. 2014).
Sustained activation of MAPK1 (ERK2) and MAPK3 (ERK1) downstream of MET-activated RAS may require MET endocytosis and signaling from endosomes (Peschard et al. 2001, Hammond et al. 2001, Petrelli et al. 2002, Kermorgant and Parker 2008).
Binding of MET to MUC20 or RANBP10 interferes with RAS activation (Higuchi et al. 2004, Wang et al. 2004).

Adapter proteins FRS2 and FRS3 can both bind to the cytoplasmic tail of activated NTRK2 (TRKB) receptor, which is followed by NTRK2-mediated phosphorylation of FRS2 and FRS3. NTRK2 signaling through FRS3 has been poorly characterized (Easton et al. 1999, Yuen and Mobley 1999, Dixon et al. 2006, Zeng et al. 2014). Phosphorylated FRS2 is known to recruit GRB2 (presumably in complex with SOS1) and PTPN11 (SHP2) to activated NTRK2, leading to augmentation of RAS signaling (Easton et al. 1999, Easton 2006).

Sprouty was initially characterized as a negative regulator of FGFR signaling in Drosophila. Human cells contain four genes encoding Sprouty proteins, of which Spry2 is the best studied and most widely expressed. Spry proteins modulate the duration and extent of signaling through the MAPK cascade after FGF stimulation, although the mechanism appears to depend on the particular biological context. Some studies have suggested that Sprouty binds to GRB2 and interferes with the recruitment of GRB2-SOS1 to the receptor, while others have shown that Sprouty interferes with the MAPK cascade at the level of RAF activation. In addition to modulating the MAPK pathway in response to FGF stimulation, Sprouty itself appears to be subject to complex post-translational modification that regulates its activity and stability.

The exact role of SHC1 in FGFR signaling remains unclear. Numerous studies have shown that the p46 and p52 isoforms of SHC1 are phosphorylated in response to FGF stimulation, but direct interaction with the receptor has not been demonstrated. Co-precipitation of p46 and p52 with the FGFR2 IIIc receptor has been reported, but this interaction is thought to be indirect, possibly mediated by SRC. Consistent with this, co-precipitation of SHC1 and FGFR1 IIIc is seen in mammalian cells expressing v-SRC. The p66 isoform of SHC1 has also been co-precipitated with FGFR3, but this occurs independently of receptor stimulation, and the p66 isoform not been shown to undergo FGF-dependent phosphorylation. SHC1 has been shown to associate with GRB2 and SOS1 in response to FGF stimulation, suggesting that the recruitment of SHC1 may contribute to activation of the MAPK cascade downstream of FGFR.

The exact role of SHC1 in FGFR signaling remains unclear. Numerous studies have shown that the p46 and p52 isoforms of SHC1 are phosphorylated in response to FGF stimulation, but direct interaction with the receptor has not been demonstrated. Co-precipitation of p46 and p52 with the FGFR2 IIIc receptor has been reported, but this interaction is thought to be indirect, possibly mediated by SRC. Consistent with this, co-precipitation of SHC1 and FGFR1 IIIc is seen in mammalian cells expressing v-SRC. The p66 isoform of SHC1 has also been co-precipitated with FGFR3, but this occurs independently of receptor stimulation, and the p66 isoform not been shown to undergo FGF-dependent phosphorylation. SHC1 has been shown to associate with GRB2 and SOS1 in response to FGF stimulation, suggesting that the recruitment of SHC1 may contribute to activation of the MAPK cascade downstream of FGFR.