KSR1 is a component of the RAS (see 190020) signaling pathway, which is involved in cell growth, proliferation, movement, and differentiation (summary by Bell et al., 1999).

Therrien et al. (1995) described a protein kinase that is required for normal signaling efficiency of activated RAS protein (see 190020). The gene, symbolized KSR by them, was isolated by genetic studies in Drosophila of the photoreceptor development pathway. In flies, activated RAS1 results in transformation of cone cells into R7 photoreceptor cells. The extra R7 cells cause the external surface of the eye to appear roughened, and the stronger the activating mutation the more roughness is observed. Using this system, the authors screened ethylmethanesulfonate-treated and x-ray-irradiated flies for mutations that would reduce or increase the roughness. One of the genes involved in modulating this phenotype was mapped, cloned, and shown to complement the mutation. Homologs of KSR were then identified in other species including C. elegans, mouse, and human. The mouse cDNA was isolated from a teratocarcinoma library and was predicted to encode an 873-amino acid protein that contains a kinase domain with similarity to a region of the RAF kinases (see 311010). The human protein was about 95% similar to the mouse over most of its sequence. Downward (1995) reviewed the molecular components of the RAS signaling pathway in light of the discovery of KSR in Drosophila and mammals by Therrien et al. (1995).

Hartz (2004) mapped the KSR1 gene to chromosome 17q11.2 based on an alignment of the KSR1 sequence (GenBank U43586) with the genomic sequence.

Muller et al. (2001) showed that KSR1 translocates from the cytoplasm to the cell surface in response to growth factor treatment and that this process is regulated by CDC25C-associated kinase-1 (CTAK1; 602678). CTAK1 constitutively associates with mammalian KSR1 and phosphorylates ser392 to confer 14-3-3 binding and cytoplasmic sequestration of KSR1 in unstimulated cells. In response to signal activation, the phosphorylation state of ser392 is reduced, allowing the KSR1 complex to colocalize with activated RAS and RAF1 (164760) at the plasma membrane, thereby facilitating the phosphorylation reactions required for the activation of MEK and MAPK (see 176872).

Using Drosophila Schneider S2 cells, Rajakulendran et al. (2009) demonstrated that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which they termed the side-to-side dimer. Moreover, they found that the RAF-related pseudokinase KSR also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation.

Using yeast 2-hybrid assays, Bell et al. (1999) found that mouse Ksr1 interacted with G protein gamma subunits (e.g., GNG3; 608941) through its CA3 domain, which contains a cysteine-rich zinc finger-like domain. In vitro association experiments and in vivo coimmunoprecipitation assays showed that Ksr1 bound to G protein beta-gamma subunits. Differential centrifugation and immunoblot analysis demonstrated that lysophosphatidic acid treatment of COS-7 cells resulted in redistribution of Ksr1 from the cytosolic fraction to the membrane fraction. Expression of full-length mouse Ksr1 in COS-7 cells inhibited beta-1 (GNB1; 139380)-gamma-3-induced MAP kinase activation, without affecting beta-1 protein levels.

Using human cells, Rinaldi et al. (2016) found that PRAJA2 (PJA2; 619341) directly interacted with and ubiquitylated KSR1, thereby reducing its levels through the ubiquitin-dependent proteolysis pathway. Reduction of KSR1 levels attenuated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) signaling by regulating KSR1-dependent phosphorylation of ERK1/ERK2 at their active sites. Praja2 also regulated ERKs in mouse embryonic stem cells (ESCs) and was involved in ERK-dependent ESC differentiation.

To analyze Ksr as a potential scaffold for the Ras/MAPK signaling pathway, Nguyen et al. (2002) developed Ksr-deficient mice. Mutant mice were grossly normal, even though Mek and Erk activation was attenuated to a degree sufficient to block T-cell activation and inhibit tumor development. Consistent with its role as a scaffold, high molecular mass complexes containing Ksr, Mek, and Erk were lost in the absence of Ksr.

Yan et al. (2004) demonstrated that KSR1 and its target signaling pathways are activated in inflamed colon mucosa of KSR1-deficient mice. Loss of KSR1 increased susceptibility to chronic colitis and TNF (191160)-induced apoptosis in the intestinal epithelial cell. Disruption of KSR1 expression enhanced TNF-induced apoptosis in mouse colon epithelial cells and was associated with a failure to activate antiapoptotic signals. These effects were reversed by wildtype, but not kinase-inactive, KSR1. Yan et al. (2004) concluded that KSR1 has an essential protective role in the intestinal epithelial cell during inflammation through activation of cell survival pathways.

Zhang et al. (2011) found that Ksr1 -/- mice were highly susceptible to pulmonary Pseudomonas aeruginosa infection accompanied by uncontrolled pulmonary cytokine release, sepsis, and death, whereas wildtype mice cleared the infection. Ksr1 recruited and assembled iNos (NOS2A; 163730) and Hsp90 (HSP90AA1; 140571) to enhance iNos activity and release nitric oxide (NO) after infection. Alveolar macrophages and neutrophils of Ksr1 -/- mice were unable to activate iNos, produce NO, and kill bacteria. Restoration of NO production restored bactericidal capability and rescued Ksr1 -/- mice from P. aeruginosa infection. Zhang et al. (2011) proposed that KSR1 functions as a scaffold that enhances iNOS activity and is crucial for the pulmonary response to P. aeruginosa infection.