# Ras Isoforms from Lab Benches to Lives--What Are We Missing and How Far Are We?
## 3 One Switch Many Outputs
This enables binding with an escort protein importin 7 (Imp7) and thus the translocation of ERK to the nucleus. Once in the nucleus, Ras-related nuclear protein (Ran GTPase) dissociates Imp7 from ERK leading to the accumulation of ERK in the nucleus [39]. Accumulated phospho-ERK activates transcription factors like c-Myc and c-Fos which are key regulators of cell cycle progression [40] and proliferation [41], respectively. In addition, other transcription factors involved in chromatin remodeling and subsequent acceleration of the cell cycle like the upstream binding factor (UBF) are also activated by ERK [42]. p38 MAPK transmits extracellular cues to intracellular targets and its signaling dictates cellular responses like proliferation, differentiation, response to stress [43], etc. A diverse range of MKK kinases activates p38 including TGF-B activating kinase (TAK1), Mitogen-activated protein kinase kinase kinase kinase 4 (MEKK4), mitogen-activated protein kinase kinase 5 (MAPKK5), and dual leucine zipper-bearing kinase/mitogen-activated protein kinase upstream protein kinase/zipper protein kinase (DLK/MUX/ZPK). On activation by Ras, p38 MAPK follows a similar translocation to the nucleus and regulates transcription factors. Ras by its association with interleukin-1 receptor-associated kinase (IRAK), TRAF6, and TGF-B activating kinase 1 (TAK1) is involved in interleukin 1 (IL-1) induced activation of p38 MAPK [44]. p38 MAPK binds to escort protein either Imp7 or Imp9 and Imp3 subsequently binds, forming an (Imp7/Imp3/kinase or Imp9/Imp3/kinase) complex. Similar to ERK translocation, Ran GTPase dissociates importin from p38 MAPK [45]. An array of transcription factors are activated by p38 MAPK which includes activating transcription factors (ATF 1/2/6) [46], Nuclear factor of activated T cells (NFAT) [47], erythroblast transformation specific transcription factor ELK1, serum responsive factor Sap1 (SRF) [48], C/EBP homologous protein (CHOP) growth arrest and DNA damage-inducible protein 153 (GADD153) [49], p53 [50], C/EBP\(\beta\), chromatin remodeling HMG box protein HBP1 [51], and various myocyte enhance factors like MEF2C, MEF2A [52], microphthalmia-associated transcription factor 1 (MITF1), DNA damage-inducible transcript 3 (DDIT3), etc. [53,54]. To Divide or Not--Ras Decides the Cellular Fate  
Ras plays a pivotal role in regulating the process of determining whether a cell should undergo proliferation or remain quiescent. Cell cycle progression depends mainly on cyclin-dependent kinases (CDK) comprising a kinase subunit that binds to a regulatory cyclin, forming a cyclin-CDK complex- an active kinase. A repertoire of other kinases and phosphatases is also involved in this process. In quiescent cells, Ras directs the progression of cells from G1 to the S phase by inducing the synthesis of DNA [55]. As mentioned earlier, transcription factors act as a substrate for Ras-activated ERK1/2 or P38 MAPK. [PERSON] et al. showed that transient expression of oncogenic Ras in the cells leads to the expression of Jun and Fos that activate the transcription factor AP1 (Activator Protein 1) [56]. Retinoblastoma gene (Rb) plays a major role in the progression of cells from G1 to the S phase. In quiescent cells, Rb remains bound to the transcription factor EF2 (Elongation Factor 2) in a hypophosphorylated state. This in turn is bound to histone deacetylase HDAC1 that represses gene transcription [57]. Activation of CDK4/6 by cyclin D hyperphosphorlytes Rb and it dissociates from the Rb-EF2-HDAC complex initiating the transcription of genes. Many studies have shown the Ras can induce the expression of cyclin D [58; 59; 60] by the Raf-MAPK pathway [61] and thus shorten the G-phase in cells. Ras upregulates cyclin A as well, which is important for Ras-induced anchorage-dependent growth [62]. A feeble expression of cyclin E is also induced by Ras [63], but the prime mechanism of progression of cells from G1 to S is by degradation of CDK inhibitor p2/Kip1 by MAPK signaling [64].