# Ras Isoforms from Lab Benches to Lives--What Are We Missing and How Far Are We?
## 3 One Switch Many Outputs  
Diverse signals like growth factors, hormones, cytokines, neurotransmitters, etc. can activate Ras. It acts as a common junction in the signal relay of many pathways. The most well-characterized pathway of Ras activation is through the growth factor receptors-receptor tyrosine kinases (RTKs). This includes the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), etc. Following growth factor stimulation, the RTKs undergo dimerization. The signal propagates downstream through the autophosphorylation of the adaptors like growth factor receptor-bound protein 2 (Grb2), which recruits GEFs like Son of Sevenless (SOS). The Grb2/SOS complex binds to and activates Ras by facilitating the exchange of GTP for GDP. GTP-bound Ras undergoes a conformational change in its effector domains switch I and II, opening up more binding sites for effectors. Signals are further propagated through  
\begin{table}
\begin{tabular}{c c c c c c c c} \hline \hline \multirow{2}{*}{**S. No. **} & \multirow{2}{*}{ \begin{tabular}{c} **Primary Tissue** \\ **Type** \\ \end{tabular}  } & \multirow{2}{*}{ \begin{tabular}{c} **(Mutated)** \\ **Total Samples** \\ **Tested** \\ \end{tabular}  } & \multirow{2}{*}{ \begin{tabular}{c} **(Mutated)** \\ **Mutations** \\ \end{tabular}  } & \multirow{2}{*}{ \begin{tabular}{c} **(Mutated)** \\ **Mutations** \\ \end{tabular}  } & \multirow{2}{*}{ \begin{tabular}{c} **(Mutated)** \\ **Tested** \\ \end{tabular}  } & \multirow{2}{*}{ \begin{tabular}{c} **(Mutated)** \\ **Mutations** \\ \end{tabular}  } & \multirow{2}{*}{\ \begin{tabular}{c} **(Mutated)** \\ **Total Samples** \\ **Tested** \\ \end{tabular}  } & \multirow{2}{*}{ \begin{tabular}{c} **\% of Point** \\ **Mutations** \\ \end{tabular}  } \\ \hline
20 & Meninges & (12)283 & 4.24 & (4)317 & 1.26 & (23)359 & 6.41 \\ \hline
21 & NS & (17)1251 & 1.36 & (103)1808 & 6.19 & (458)2674 & 17.13 \\ \hline
22 & Oesophagus & (9)2668 & 0.34 & (71)3203 & 2.28 & (5)2142 & 0.23 \\ \hline
23 & Ovary & (4)1677 & 0.24 & (899)6913 & 13.57 & (31)1916 & 1.62 \\ \hline
24 & Pancreas & (3)3135 & 0.1 & (676)712289 & 56.38 & (26)3513 & 0.74 \\ \hline
25 & Paratesticular tissues *  
effectors of Ras containing the Ras-binding domain (RBD) like the serine/threonine kinases rapidly accelerated fibrosarcoma (Raf1) or phosphoinositide 3 kinase (PI3K) followed by a cascade of phosphorylation of MAPK modules [28]. Ral guanine nucleotide dissociation stimulator (RalGDS) is another effector of Ras which contains the RBD domain. It further acts as a GEF for the activation of Ral GTPases. Studies in skin cancer models have proven the indispensable role of RalGDS in Ras-induced oncogenesis [29]. The main MAPK cascades studied so far include extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and ERK5 [30]. One of the key signaling molecules activated by Ras-Raf1 is mitogen-activated protein kinase kinase 12 (MEK1/2) that further activates ERK1/2. MEK1 has a proline-rich sequence that is necessary for its binding to Raf [31]. The three lysines and other hydrophobic residues in the \(N\)-terminal part of MEK enable its binding to ERK1/2 [32]. Upon stimulation of ERK1/2, MEK translocates to the nucleus but is quickly sent back to the cytoplasm [33]. The intrinsic kinase activity of ERK is enhanced 1000-fold due to its phosphorylation by MEK1/2. ERK1 is phosphorylated at Thr202 and Tyr204 and ERK2 at Thr183 and Tyr185 [34,35]. ERK phosphorylates a wide spectrum of substrates in the cytoplasm, organelles, and nucleus [36]. Ras-Raf-ERK-mediated proliferative functions are mainly an outcome of the stimulation-induced translocation of ERK to the nucleus [37]. MEK induces phosphorylation of the threonine and tyrosine residues of ERK, exposing its SPS (Sper244, Pro245, and Ser246) motif, within the nuclear translocation signal (NTS) [38].