II that is thought to be critical for the phosphotransfer reaction. Them and (3) the mammalian homologs contain an arginine residue instead of an invariant lysine residue in kinase subdomain (2) they contain a conserved region of ∼40 amino acids at their N terminus called Conserved Area 1 (CA1) that is unique to 1995), but differ in at least three main aspects: (1) they do not contain the so-called RAS-binding domain found in RAF proteins Interestingly, KSR proteins are mostly related to RAF serine/threonine kinase family members ( Therrien et al. 1995 Sundaram and Han 1995 Therrien et al.
KSR was originally identified in RAS-dependent genetic screens in Drosophila and C. One of these is Kinase Suppressor of RAS (KSR), whose activityĪppears to be required in the ERK/MAPK pathway (for review, see Morrison 2001). Other proteins have been suggested to function as scaffolds in specific MAPK pathways (for review, see Garrington and Johnson 1999) however, their precise molecular function remains ambiguous. 1999), which function in the JNK pathway and finally MEK partner 1 (MP1), which apparently bridges MEK1 and ERK1 ( Schaeffer et al. cerevisiae ( Posas and Saito 1997) the JNK-interacting proteins (JIP-1/2 Whitmarsh et al. The clearest examples include the yeast protein PBS2 required in the osmosensing-response MAPK pathway in S. Have been identified (for review, see Garrington and Johnson 1999 Schaeffer and Weber 1999). Ever since the discovery of STE5, only a handful of potential scaffolding proteins with respect to specific MAPK pathways Module required for mating in Saccharomyces cerevisiae ( Choi et al. The prototype for such scaffolding proteins is STE5, which simultaneously binds to STE11, STE7, and FUS3, the three-kinase Provided a framework to explain signal transmission specificity and possibly efficiency (for review, see Whitmarsh and Davis 1998). The identification of proteinsĬapable of binding at the same time to at least two of the three kinases of the module, thereby physically linking them together, This raised questions early on about how signal transmission specificity could be achieved. 1999 Kolch 2000).Īs for the ERK pathway, most groups of MAPK pathways comprise multiple and closely related kinase isoforms that are oftenĮxpressed in the same cells ( Garrington and Johnson 1999). Such as cell growth, proliferation, differentiation, and survival (for review, see English et al. Principal mediator of signals emanating from the small GTPase RAS, thereby influencing multiple aspects of cell physiology This pathway is composed of specific combinations of RAF, MEK, and ERK/MAPK isoforms and is one of the At leastįive groups of MAPK pathways have been distinguished in mammals, which include the extensively studied extracellular-regulated The prototypical MAPK pathway is a three-kinase module that transmits signals through a phosphorylation cascade.
The evolutionarilyĬonserved mitogen-activated protein kinase (MAPK) pathways are among the best described examples (for review, see Schaeffer and Weber 1999). Suggest that KSR functions as a scaffold that assembles the RAF/MEK functional pair.Ĭells use a range of signaling pathways to convey distinct information to appropriate intracellular targets. Lead to the formation of a RAF/MEK complex, thereby positioning RAF in close proximity to its substrate MEK. We further show that KSR associates independently with RAF and MEK, and that these interactions In agreement with this, we found that KSR facilitates Here, we show that KSR functions upstream of MEK within the ERK/MAPK module. In RAS-dependent genetic screens in Drosophila and Caenorhabditis elegans. One of these is Kinase Suppressor of Ras (KSR), a component previously identified Suspected to play critical roles in this process. Mechanisms that regulate signal propagation through the ERK/MAPK pathway are still poorly understood.
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