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Multiple Domains of Ruk/CIN85/SETA/CD2BP3 are Involved in Interaction with p85α Regulatory Subunit of PI 3-kinase

Borthwick, Emma B., Korobkob, Igor V., Luke, Courtney, Drelc, Victor R., Fedyshyn, Yaroslav Ya., Ninkina, Natalia ORCID:, Drobot, Ludmila B. and Buchman, Vladimir ORCID: 2004. Multiple Domains of Ruk/CIN85/SETA/CD2BP3 are Involved in Interaction with p85α Regulatory Subunit of PI 3-kinase. Journal of Molecular Biology 343 (4) , pp. 1135-1146. 10.1016/j.jmb.2004.08.075

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A high degree of structural similarity between two recently identified proteins, CD2AP/CMS/METS-1 and Rukl/CIN85/SETA/CD2BP3, allowed them to become founders of a novel protein family.1 Their structural organisation is typical for adapter proteins: the bulk of the molecule comprises of multiple protein–protein interaction motifs, including three SH3 domains, Pro-rich region and coiled-coil domain. CD2AP/CMS/METS-1 has been implicated in clustering of CD2 receptors and rearrangement of T-cell cytoskeleton in the region of contact with an antigen-presenting cell.2 Similarly, in podocytes this protein is involved in clustering and anchoring to the cytoskeleton of nephrin, a kidney-specific receptor of the immunoglobulin superfamily.[3], [4], [5], [6] and [7] Nephrological and immunological phenotypes of CD2AP null mutant mice confirm the suggestion that CD2AP/CMS/METS-1 function is crucial for formation of such specialised types of cell–cell contacts as slit diaphragm and immunological synapse.4 In the absence of information about the phenotype of null mutant mice, the biological function of Ruk/CIN85/SETA/CD2BP3 is less clear. However, involvement of this protein in several important intracellular processes has been demonstrated in model systems. The best characterised function of this protein is down-regulation of receptor tyrosine kinases (RTKs) via activation of their internalisation.[8], [9] and [10] Ruk/CIN85/SETA/CD2BP3 specifically regulates clathrin-dependent endocytosis of ligand-activated receptors and available data suggest that for implementation of this function a direct and simultaneous interaction with two proteins, Cbl and endophilin, is crucial.[1], [11] and [12] Ubiquitin ligases of Cbl family not only interact with but also monoubiquitinate Ruk/CIN85/SETA/CD2BP3.13 However, such ubiquitination does not play a role of a signal for proteasome degradation14 but is required for targeting of the protein to the lysosome degradation pathway in trimeric complex with RTK and Cbl proteins.13 The ability of Ruk/CIN85/SETA/CD2BP3 to interact with other proteins, such as BLNK,15 SB1, CD2,16 CAPZ,17 Grb2, p130Cas,[15] and [16] FAK and Pyk-2 kinases,18 and Src family kinases (our unpublished observations) and similarity with CD2AP/CMS/METS-1 (including common binding site in the cytoplasmic segment of CD219) implicates this protein in regulation of B- and T-cell receptor signalling, rearrangements of actin cytoskeleton and cell adhesion. The role of Rukl/CIN85/SETA/CD2BP3 and its isoforms in regulation of apoptosis has been demonstrated in two types of cells. In astrocytes, overexpression of SETA protein or its mutants sensitises cells to apoptosis induced by UV irradiation.20 It has been suggested that this effect depends on the ability of the SH3-B domain of SETA to interact with a proline-rich region of AIP1/Alix protein, an important modulator of apoptosis in glial cells.20 Apoptosis of peripheral neurons in primary culture could be induced by overexpression of Rukl.21 Because the PI 3-kinase signalling pathway is important for survival of these cells, it is feasible that the negative regulation of PI 3-kinase activity by Rukl might trigger apoptotic death. Originally, the effect of Rukl on PI 3-kinase activity and neuronal survival was attributed to interaction of its Pro-rich region and the SH3 domain of the p85? regulatory subunit of PI 3-kinase. However, at least one natural isoform of the protein possessing proline-rich region, Rukm, does not have pro-apoptotic activity itself and is able to block pro-apoptotic activity of Rukl.21 This suggests that other domains of Ruk and p85? might also be involved, directly or indirectly, in interaction of these two proteins. Due to the complexity of Ruk expression patterns in various types of cells and tissues,22 two or more isoforms may be expressed in the same cell and modulate each other's signalling abilities. Because of the importance of Ruk interaction with other signalling proteins for cell physiology we decided to scrutinise the role of various Ruk domains in heteromerisation of Ruk isoforms with the p85? regulatory subunit of PI 3-kinase. Our results demonstrate that all three types of protein–protein interaction motifs within the Ruk molecule, SH3 domains, Pro-rich region and coiled-coil domain, affect heteromerisation of two proteins.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Uncontrolled Keywords: Protein–protein interaction ; Phosphatidylinositol 3-kinase ; Adaptor protein ; SH3 domain ; Proline-rich region
ISSN: 0022-2836
Last Modified: 01 Dec 2022 10:00

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