T-lymphoma invasion and metastasis-inducing protein 1 (Tiam1) is a guanine exchange factor (GEF) for CDC42 and the Rho-family GTPase Rac1, which plays an important role in cell-matrix adhesion and in cell migration [, ]. Tiam1 is involved in multiple steps of tumorigenesis [].
Tiam1 is a guanine exchange factor (GEF) for CDC42 and the Rho-family GTPase Rac1, which plays an important role in cell-matrix adhesion and in cell migration [, ]. Tiam1 is involved in multiple steps of tumorigenesis [].This entry represents the CC and Ex subdomain found in the PH-CC-Ex globular domain of the Tiam1 and Tiam2 proteins (T-lymphoma invasion and metastasis). The CC subdomain forms an antiparallel coiled coil with two long α-helices, together with the C-terminal Ex subdomain they form a small globular domain comprising three α-helices. The CC subdomain of the Tiam2 PHCCEx domain follows the C-terminal alpha1 helix of the PH subdomain through a four-residue linker [].
The Caskin1 protein interacts with the CASK protein via this region []. CASK and Caskin1 are synaptic scaffolding proteins. The binding motif on human Caskin1 is EEIWVLRK. A similar motif is found on protein MINT1 and protein TIAM1, both shown to be able to bind to CASK though the motif. However, MINT1 and TIAM1 are not included in this entry []. This region is predicted to be natively unstructured.This entry also matches Caskin2, a Caskin1 homologue deprived of the CASK interaction domain (CID) []. Caskin1 and caskin2 consist of multiple ankyrin repeats, two SAM domains and one SH3 domain. In Caskin1 the CID is located between the SH3 and SAM domains [].
T-lymphoma invasion and metastasis-inducing protein 1 (Tiam1) is a guanine exchange factor (GEF) for CDC42 and the Rho-family GTPase Rac1, which plays an important role in cell-matrix adhesion and in cell migration [, ]. Tiam1 is involved in multiple steps of tumorigenesis [].Tiam2 has been shown to localise to the nuclear envelope and to regulate Rac1 activity at the nuclear envelope which regulates the perinuclear actin cap []. It has been shown to promote invasion and motility of non-small cell lung cancer cells []. It has also been shown to promote epithelial-to-mesenchymal transition and results in proliferation and invasion in liver cancer cells []. This entry includes a group of guanine nucleotide exchange factors, including Tiam1/2 from humans and Sif from Drosophila [, , ]. Tiam1/2 are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity [].
Slm1 is a component of the target of rapamycin complex 2 (TORC2) signaling pathway. It plays a role in the regulation of actin organization and is a target of sphingolipid signaling during the heat shock response []. Slm1 contains a single PH domain that binds PtdIns(4,5)P2, PtdIns(4)P, and dihydrosphingosine 1-phosphate (DHS-1P). Slm1 possesses two binding sites for anionic lipids. The non-canonical binding site of the PH domain of Slm1 is used for ligand binding, and it is proposed that beta-spectrin, Tiam1 and ArhGAP9 also have this type of phosphoinositide binding site []. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner []. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity []. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane []. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes [].
