Phospho-KSR1 (Thr425) Antibody - #AF4341

Part of a multiprotein signaling complex which promotes phosphorylation of Raf family members and activation of downstream MAP kinases (By similarity). Independently of its kinase activity, acts as MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or MAP2K2/MEK2. Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP (By similarity). Its kinase activity is unsure (By similarity). Some protein kinase activity has been detected in vitro, however the physiological relevance of this activity is unknown (By similarity).

Phosphorylated on Ser-311 and, to a higher extent, on Ser-406 by MARK3. Dephosphorylated on Ser-406 by PPP2CA. In resting cells, phosphorylated KSR1 is cytoplasmic and in stimulated cells, dephosphorylated KSR1 is membrane-associated. Phosphorylated by PKA at Ser-888. Phosphorylation at Ser-888 is required for cAMP-dependent activation of MAPK1 and/or MAPK3 (By similarity).

Cytoplasm. Membrane>Peripheral membrane protein. Cell membrane>Peripheral membrane protein. Cell projection>Ruffle membrane. Endoplasmic reticulum membrane.
Note: In unstimulated cells, where the phosphorylated form is bound to a 14-3-3 protein, sequestration in the cytoplasm occurs. Following growth factor treatment, the protein is free for membrane translocation, and it moves from the cytoplasm to the cell periphery.

Homodimer. Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent manner. Interacts with MAP2K1/MEK1 and MAP2K2/MEK2. Binding to MAP2K1/MEK1 releases the intramolecular inhibitory interaction between KSR1 N-terminus and kinase domains which is required for the subsequent RSK1 dimerization with BRAF. Identified in a complex with AKAP13, MAP2K1 and BRAF (By similarity). Interacts with AKAP13 and BRAF. Interacts with RAF and MAPK/ERK, in a Ras-dependent manner (By similarity). Interacts with 14-3-3 proteins including YWHAB (By similarity). Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37. The binding of 14-3-3 proteins to phosphorylated KSR1 prevents the membrane localization (By similarity). Interacts with MARK3 (By similarity). Interacts with PPP2R1A and PPP2CA (By similarity). Interacts with isoform 1 of VRK2.

The protein kinase domain is predicted to be catalytically inactive. The domain is sufficient for KSR1 and KSR1-mediated MAP2K1 and MAP2K2 membrane localization. The domain is required but not sufficient for MAP kinase-mediated inhibition of ELK1 phosphorylation (PubMed:10409742).

The N-terminal region mediates interaction with BRAF (PubMed:29433126). Also mediates membrane localization (By similarity).

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.