Disease relevance of CD2AP

• Here we addressed the role of nephrin, CD2-associated protein (CD2AP), and podocin together with the integrity of the slit diaphragm in the pathogenesis of proteinuria of patients with diabetes and nephropathy [1].
• Mice lacking CD2AP exhibit a congenital nephrotic syndrome characterized by extensive foot process effacement, suggesting that CD2AP-nephrin interactions are critical to maintaining slit diaphragm function [2].
• Assuming that a decrease in CD2AP attenuates clearance of glomerular immune complexes, patients with other types of idiopathic glomerulonephritis should also have a CD2AP mutation [3].
• Some recent studies demonstrated that CD2-associated protein (CD2AP) is also a functional molecule in the slit diaphragm, and its expression is altered in membranous nephropathy [4].
• Here we are interested in the function of the podocyte and trying to understand how genetic deficiency of CD2AP in podocytes leads to kidney failure [5].

Psychiatry related information on CD2AP

• CMS rats spent more time in REM sleep and showed more fragmented sleep compared to their baseline recording, while there were no changes in the control rats [6].
• In an animal model of depression, chronic exposure to mild stressors (CMS, e.g. periods of soiled cage, reversed light/dark cycle, grouped housing, food and/or water deprivation) causes behavioral and hormonal changes which, in humans, often are associated with depression [6].
• Increased sleep fragmentation in CMS rats was particularly evident by increased number of arousals, and increased REM sleep and slow-wave-sleep-1 (SWS-1) episodes [6].
• In fall 1998 CMS implemented the National Medicare Education Program (NMEP) to educate beneficiaries about their Medicare program benefits; health plan choices; supplemental health insurance; beneficiary rights, responsibilities, and protections; and health behaviors [7].

High impact information on CD2AP

• This novel protein, called CD2AP, is likely to facilitate receptor patterning in the contact area by linking specific adhesion receptors to the cytoskeleton [8].
• However, mRNA and protein levels for CD2AP and podocin were greatly reduced, suggesting a cooperative role for these molecules in foot process and slit diaphragm formation [9].
• That podocin interacts with CD2AP and nephrin in vivo is shown by coimmunoprecipitation of these proteins from glomerular extracts [10].
• Whether disruption in a particular mitochondrial function is at the root of CMS in all species, or whether defects in numerous mitochondrial activities can produce sterility, will only be revealed by further probing of physiological and biochemical defects present in CMS genotypes [11].
• A characteristic of CMS mutations in plants, in contrast to the single base changes in human mitochondrial mutants (49, 140), is the presence of chimeric genes or chimeric loci; different open reading frames are joined together, or placed in proximal locations and cotranscribed with standard mitochondrial genes [11].

Chemical compound and disease context of CD2AP

• We screened for WT1 mutations in 200 patients with nephrotic syndrome: 114 with steroid resistance (SRNS) and 86 with steroid dependence (SDNS) for whom other inherited forms of nephrotic syndrome (NPHS2, CD2AP) had been previously excluded [12].

Biological context of CD2AP

• Our findings reveal a novel role for the slit diaphragm proteins nephrin, CD2AP, and podocin and demonstrate that these three proteins, in addition to their structural functions, initiate PI3K/AKT-dependent signal transduction in glomerular podocytes [13].
• A Cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton [14].
• First, endogenous CD2AP was found concentrated in the narrow region of the midzone microtubules during anaphase and in the midbody during late telophase [15].
• Both CD2AP and anillin were found phosphorylated early in mitosis and also CD2AP phosphorylation was coupled to its delocalization from membrane to cytosol [15].
• The results indicate an endogenous interaction between nephrin and CD2AP in M-1 cells and suggest that this interaction is mediated by the third Src homology 3 (SH3) domain of CD2AP [16].

Anatomical context of CD2AP

• Overexpression of a fragment from the C-terminal half or the N-terminal SH3 domain of CD2AP in a mouse T cell hybridoma resulted in enhanced interleukin-2 production and reduced T cell receptor down-modulation in response to antigen [17].
• When exposed to all nephrotic plasma samples (and a non-human serum control), nephrin podocin and CD2AP assumed a cytoplasmic distribution; nephrin and synaptopodin were selectively downregulated, and the relocation of nephrin induced by nephrotic plasma could be rescued back to the plasma membrane by co-incubation with non-nephrotic plasma [18].
• However, coexpression of Rab4-Q67L with CD2AP/CMS induces a significant enlargement of EEA1-positive early endosomes [19].
• Third, the CD2AP small interfering RNA interfered with the cell separation, indicating that CD2AP is required for HeLa cells cytokinesis [15].
• Extensive extrarenal expression of CD2AP was observed in endothelial and epithelial cells, in many cases with a specific subcellular localization [2].

Associations of CD2AP with chemical compounds

• Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling [13].
• The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction [20].
• This colocalization was significantly impaired by an inhibitor of VEGFR kinase SU5416, the Y1333F mutation in Flt-1, or by a dominant negative form of CD2AP [21].
• The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP [22].
• This review will focus on the remnant kidney model, the podocyte injury models of puromycin aminonucleoside or adriamycin injection, and examples of newly developed genetic models, such as knockout of CD2 associated protein (CD2AP) [23].

Physical interactions of CD2AP

• The CD2AP-binding site for cortactin mapped to the second of three proline-rich regions [14].
• CAPZ bound the C-terminal half of CMS and CIN85 [17].
• CD3 stimulation is known to enhance CD2 avidity for its ligand and to induce the binding of the CD2AP protein to the CD2 cytoplasmic tail [24].
• CMS can also form heterotypic complexes with CIN85 [25].

Co-localisations of CD2AP

• In conditionally immortalized mouse podocytes, we demonstrate that CD2AP colocalizes with cortactin and F-actin in spots of < or =0.5-microm diameter [26].

Regulatory relationships of CD2AP

• CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl [19].

Other interactions of CD2AP

• With the use of a conditionally immortalized human podocyte cell line, it first was shown that exposure to normal and non-nephrotic human plasma leads to a concentration of nephrin, podocin, CD2AP, and actin at the cell surface [18].
• There are also 3 genetic loci connected with autosomal dominant forms of FSGS: ACTN4, TRPC6 and CD2AP (found only in the mice models) [27].
• We propose that CD2AP/CMS, through interactions with Rab4 and c-Cbl, controls early endosome morphology and may play a role in traffic between early and late endosomes, and thus in the degradative pathway [19].
• We have identified a novel c-Cbl-interacting protein termed CIN85 with a molecular mass of 85 kDa which shows similarity to adaptor proteins, CMS and CD2AP [28].
• Secondary changes in the distribution of nephrin, CD2AP, and alpha-actinin are additional evidences for the scaffolding role of podocin in the organization of the slit diaphragm [29].

Analytical, diagnostic and therapeutic context of CD2AP

• Podocytes are critical in maintaining the filtration barrier of the glomerulus and are dependent on the slit diaphragm (SD) proteins nephrin, podocin, and CD2-associated protein (CD2AP) to function optimally [18].
• Using real-time PCR and immunolabeling, we showed that the expression of other slit diaphragm components was modified in Nphs2-/- kidneys: the expression of the nephrin gene was downregulated, whereas that of the ZO1 and CD2AP genes appeared to be upregulated [30].
• In addition, nephrin was found to partially colocalize with CD2AP and podocin in double immunofluorescence microscopy, confirming the close proximity of these proteins and proposing that these proteins may belong to nephrin-associated protein complex in glomeruli [16].
• We also show by immunoelectron microscopy that nephrin and CD2AP are detected at the slit diaphragm area, supporting their interaction in the glomeruli in vivo [16].
• CD2AP and podocin expression by immunohistochemistry was also assessed [1].

References