CD2-associated protein (CD2AP) is a multifunctional adaptor linking membrane receptors to the actin cytoskeleton, ensuring slit diaphragm integrity, regulating synaptic proteostasis, and facilitating cytoskeletal remodeling. Dysregulation of CD2AP contributes to proteinuric kidney disease, Alzheimer’s disease, and tumor progression. This review provides a comprehensive overview of the structural and functional characteristics of CD2AP, its phosphorylation landscape, and potential regulatory roles. By integrating 3,825 publicly available phosphoproteomic research articles with data obtained from kinase prediction tools, the study offers information on predominant phosphosites, upstream kinases, binary interactors, and disease associations of CD2AP. We identified 45 class I phosphosites with S224, S233, S256, S458, S510, and S514 being frequently regulated across biological contexts. Predictive kinase-substrate mapping and co-regulation analysis highlighted several upstream kinases whose phosphorylation patterns positively co-regulate with CD2AP modification. Co-regulated proteins associated with Alzheimer’s and kidney disease, and several phosphoproteins were associated with cell movement and cancer progression. Overall, these findings position CD2AP as a dynamic signaling hub coordinating disease-related pathways.
AmithSR, WilkinsonJM, FliegelL. Na+/H+ exchanger NHE1 regulation modulates metastatic potential and epithelial-mesenchymal transition of triple-negative breast cancer cells. Oncotarget2016;7(16):21091–21113.
2.
Atas-OzcanH, BraultV, DuchonA, et al.Dyrk1a from gene function in development and physiology to dosage correction across life span in down syndrome. Genes (Basel)2021;12(11):1833.
3.
BaruaM, BrownEJ, CharoonratanaVT, et al.Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney Int2013;83(2):316–322.
4.
BruckS, HuberTB, InghamRJ, et al.Identification of a novel inhibitory actin-capping protein binding motif in CD2-associated protein. J Biol Chem2006;281(28):19196–19203.
5.
CasamayorA, MorriceNA, AlessiDR. Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: Identification of five sites of phosphorylation in vivo. Biochem J1999;342(Pt 2)Pt:287–292.
6.
ChenC, XuJ, ZhangJX, et al.CD2AP is a potential prognostic biomarker of renal clear cell carcinoma. Cancer Med2024;13(4):e7055.
7.
ChenH, WuG, JiangY, et al.Analyzing 54,936 samples supports the association between CD2AP rs9349407 polymorphism and Alzheimer’s disease susceptibility. Mol Neurobiol2015;52(1):1–7.
DaulatAM, WagnerMS, AudebertS, et al.The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins. J Cell Sci2022;135(17):jcs259347.
10.
DengP, ZhongC, HeP, et al.Uncovering citron kinase as a key biomarker for predicting outcomes and therapy efficacy in non-muscle-invasive bladder cancer. Gene2025;963:149590.
11.
DengY, HouZ, LiY, et al.Superbinder based phosphoproteomic landscape revealed PRKCD_pY313 mediates the activation of Src and p38 MAPK to promote TNBC progression. Cell Commun Signal2024;22(1):115.
12.
DikicI. CIN85/CMS family of adaptor molecules. FEBS Lett2002;529(1):110–115.
13.
DustinML, OlszowyMW, HoldorfAD, et al.A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell1998;94(5):667–677.
14.
ElbediwyA, ZihniC, TerrySJ, et al.Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex. J Cell Biol2012;198(4):677–693.
15.
FarooqQUA, ShaukatZ, AimanS, et al.Protein-protein interactions: Methods, databases, and applications in virus-host study. World J Virol2021;10(6):288–300.
16.
FengD. Phosphorylation of key podocyte proteins and the association with proteinuric kidney disease. Am J Physiol Renal Physiol2020;319(2):F284–F291.
17.
FukusumiY, MiyauchiN, HashimotoT, et al.Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules. World J Nephrol2014;3(3):77–84.
18.
FurlanoM, ArlandisR, VenegasMDP, et al.MYH9 Associated nephropathy. Nefrologia (Engl Ed)2019;39(2):133–140.
19.
FurusawaK, TakasugiT, ChiuY-W, et al.CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway. J Biol Chem2019;294(28):10886–10899; doi: 10.1074/jbc.RA118.005385
20.
FurusawaK, TakasugiT, ChiuYW, et al.CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway. J Biol Chem2019;294(28):10886–10899.
21.
FurushoT, SoharaE, MandaiS, et al.Renal TNFalpha activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease. Kidney Int2020;97(4):713–727.
22.
GagliardiPA, di BlasioL, PrimoL. PDK1: A signaling hub for cell migration and tumor invasion. Biochim Biophys Acta2015;1856(2):178–188.
23.
GalloD, YoungJTF, FourtounisJ, et al.CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature2022;604(7907):749–756.
24.
GaoS, ZhaoX, HouL, et al.The interplay between SUMOylation and phosphorylation of PKCdelta facilitates oxidative stress-induced apoptosis. Febs J2021;288(22):6447–6464.
25.
GirardiC, JamesP, ZaninS, et al.Differential phosphorylation of Akt1 and Akt2 by protein kinase CK2 may account for isoform specific functions. Biochim Biophys Acta2014;1843(9):1865–1874.
26.
GokceI, KayaM, CicekN, et al.Collapsing glomerulopathy in a patient with a TRPC6 mutation presenting as rapidly progressive glomerulonephritis: A case report and review of the literature. Saudi J Kidney Dis Transpl2023;34(3):254–258.
27.
GoutI, MiddletonG, AduJ, et al.Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein. Embo J2000;19(15):4015–4025.
28.
GroveM, DemyanenkoG, EcharriA, et al.ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory. Mol Cell Biol2004;24(24):10905–10922.
29.
Guimas AlmeidaC, Sadat MirfakharF, PerdigaoC, et al.Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production. Cell Mol Life Sci2018;75(14):2577–2589.
30.
HarrisonBJ, VenkatG, LambJL, et al.The adaptor protein CD2AP is a coordinator of neurotrophin signaling-mediated axon Arbor plasticity. J Neurosci2016;36(15):4259–4275.
31.
HavrylovS, RedowiczMJ, BuchmanVL. Emerging roles of Ruk/CIN85 in vesicle-mediated transport, adhesion, migration and malignancy. Traffic2010;11(6):721–731.
32.
HensleyK, VenkovaK, ChristovA, et al.Collapsin response mediator protein-2: An emerging pathologic feature and therapeutic target for neurodisease indications. Mol Neurobiol2011;43(3):180–191.
33.
Hernandez-ValladaresM, KimT, KannanB, et al.Structural characterization of a capping protein interaction motif defines a family of actin filament regulators. Nat Struct Mol Biol2010;17(4):497–503.
34.
HetmanskiJHR, JonesMJ, HartshornM, et al.Differential roles of cyclin-CDK1 complexes in cell migration and invasion. J Cell Sci2025;138(13):jcs263697.
35.
HollingworthP, HaroldD, SimsR, et al.; EADI1 consortium. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet2011;43(5):429–435.
36.
HoltzmanDM, MorrisJC, GoateAM. Alzheimer’s disease: The challenge of the second century. Sci Transl Med2011;3(77):77sr1.
37.
HoornEJ, EllisonDH. WNK kinases and the kidney. Exp Cell Res2012;318(9):1020–1026.
38.
HuberTB, HartlebenB, KimJ, et al.Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol2003;23(14):4917–4928.
39.
HyodoT, ItoS, HasegawaH, et al.Misshapen-Like Kinase 1 (MINK1) is a novel component of striatin-interacting phosphatase and kinase (STRIPAK) and is required for the completion of cytokinesis. J Biol Chem2012;287(30):25019–25029.
40.
HyvonenME, IhalmoP, SandholmN, et al.CD2AP is associated with end-stage renal disease in patients with type 1 diabetes. Acta Diabetol2013;50(6):887–897.
41.
JayaramS, GuptaMK, RajuR, et al.Multi-OMICS data integration and mapping of altered kinases to pathways reveal gonadotropin hormone signaling in glioblastoma. OMICS2016;20(12):736–746.
42.
JensenCC, ClementsAN, LiouH, et al.PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion. J Cell Biol2023;222(6):e202208136.
43.
JohnsonJL, YaronTM, HuntsmanEM, et al.An atlas of substrate specificities for the human serine/threonine kinome. Nature2023;613(7945):759–766.
44.
KawachiH, FukusumiY. New insight into podocyte slit diaphragm, a therapeutic target of proteinuria. Clin Exp Nephrol2020;24(3):193–204.
45.
KhaM, MagnussonY, JohanssonI, et al.Injured proximal tubular epithelial cells lose hepatocyte nuclear factor 4alpha expression crucial for brush border formation and transport. Am J Pathol2025;195(5):845–860.
46.
KimJM, WuH, GreenG, et al.CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science2003;300(5623):1298–1300.
47.
KimSB, MunBR, KimSY, et al.Therapeutic effects of a novel synthetic alpha-secretase. Front Aging Neurosci2024;16:1383905.
48.
KirschKH, GeorgescuMM, IshimaruS, et al.CMS: An adapter molecule involved in cytoskeletal rearrangements. Proc Natl Acad Sci U S A1999;96(11):6211–6216.
49.
KobayashiS, SawanoA, NojimaY, et al.The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1). Faseb J2004;18(7):929–931.
50.
KurillaA, LaszloL, TakacsT, et al.Studying the association of TKS4 and CD2AP scaffold proteins and their implications in the partial Epithelial-Mesenchymal Transition (EMT) process. Int J Mol Sci2023;24(20):15136.
51.
Le GrandM, RoviniA, Bourgarel-ReyV, et al.ROS-mediated EB1 phosphorylation through Akt/GSK3beta pathway: Implication in cancer cell response to microtubule-targeting agents. Oncotarget2014;5(10):3408–3423.
52.
LehtonenS, ZhaoF, LehtonenE. CD2-associated protein directly interacts with the actin cytoskeleton. Am J Physiol Renal Physiol2002;283(4):F734–F743.
53.
LiC, RuotsalainenV, TryggvasonK, et al.CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. Am J Physiol Renal Physiol2000;279(4):F785–F792.
54.
LiH, ChenH, ZhaoT, et al.CD2AP shapes a stromal reduced tumor microenvironment and contributes to immunotherapy in gastric cancer. BMC Cancer2025;25(1):910.
55.
LiL, SuN, ZhouT, et al.Mixed lineage kinase ZAK promotes epithelial-mesenchymal transition in cancer progression. Cell Death Dis2018;9(2):143.
56.
LiT, ZhangJ, ZhuF, et al.P21-Activated Protein Kinase (PAK2)-mediated c-Jun phosphorylation at 5 threonine sites promotes cell transformation. Carcinogenesis2011;32(5):659–666.
57.
LiaoF, JiangH, SrivatsanS, et al.Effects of CD2-associated protein deficiency on amyloid-beta in neuroblastoma cells and in an APP transgenic mouse model. Mol Neurodegener2015;10:12.
58.
LinZ, LvJ, DaiC, et al.Identification of the disulfidptosis-related key gene CD2AP as a potential biomarker and new therapeutic target for LUAD patients by comprehensive multi-omics analysis. Discov Oncol2025;16(1):515.
59.
LindingR, JensenLJ, PasculescuA, et al.NetworKIN: A resource for exploring cellular phosphorylation networks. Nucleic Acids Res2008;36(Database issue):D695–D699.
60.
LiuH, ShinSH, ChenH, et al.CDK12 and PAK2 as novel therapeutic targets for human gastric cancer. Theranostics2020;10(14):6201–6215.
61.
LiuY, YangH, FangY, et al.Function and inhibition of Haspin kinase: Targeting multiple cancer therapies by antimitosis. J Pharm Pharmacol2023;75(4):445–465.
62.
LiuYX, ZhangAQ, LuoFM, et al.Case report: A novel heterozygous mutation of CD2AP in a Chinese family with proteinuria leads to focal segmental glomerulosclerosis. Front Pediatr2021;9:687455.
63.
LowikMM, GroenenPJ, PronkI, et al.Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation. Kidney Int2007;72(10):1198–1203.
64.
LvLL, CaoYH, PanMM, et al.CD2AP mRNA in urinary exosome as biomarker of kidney disease. Clin Chim Acta2014;428:26–31.
65.
MahinA, GopalakrishnanAP, AhmedM, et al.Orchestrating intracellular calcium signaling cascades by phosphosite-centric regulatory network: A comprehensive analysis on kinases CAMKK1 and CAMKK2. OMICS2025;29(4):139–153.
66.
ManingerJK, NowakK, GoberdhanS, et al.Cell type-specific functions of Alzheimer’s disease endocytic risk genes. Philos Trans R Soc Lond B Biol Sci2024;379(1899):20220378.
67.
MohantyS, MohapatraP, ShriwasO, et al.CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis. Oncogene2022;41(45):4929–4940.
68.
MonzoP, GauthierNC, KeslairF, et al.Clues to CD2-associated protein involvement in cytokinesis. Mol Biol Cell2005;16(6):2891–2902.
69.
Morales-AlvarezMC, KnobA, RennkeHG, et al.Clinical and pathological heterogeneity in FSGS due to INF2 mutations. Kidney Int Rep2022;7(12):2741–2745.
70.
MustonenH, LepistoA, LehtonenS, et al.CD2AP contributes to cell migration and adhesion in cultured gastric epithelium. Biochem Biophys Res Commun2005;332(2):426–432.
71.
OthaimAA, AlasiriG, AlfahedA. Therapeutic, clinicopathological, and molecular correlates of PRKACA expression in gastrointestinal cancers. Pharmaceuticals (Basel)2024;17(10):1263.
72.
Ozfiliz KilbasP, SonmezO, Uysal-OnganerP, et al.Specific c-Jun N-Terminal kinase inhibitor, JNK-IN-8 suppresses mesenchymal profile of PTX-Resistant MCF-7 cells through modulating PI3K/Akt, MAPK and Wnt signaling pathways. Biology (Basel)2020;9(10):320.
73.
PalollathilA, NajarMA, AmruthaS, et al.Bacopa monnieri confers neuroprotection by influencing signaling pathways associated with interleukin 4, 13 and extracellular matrix organization in Alzheimer’s disease: A proteomics-based perspective. Neurochem Int2024;180:105864.
74.
ParcaL, ArianoB, CabibboA, et al.Kinome-wide identification of phosphorylation networks in eukaryotic proteomes. Bioinformatics2019;35(3):372–379.
75.
PaveskovicM, De-PaulaRB, OjeladeSA, et al.Alzheimer’s disease risk gene CD2AP is a dose-sensitive determinant of synaptic structure and plasticity. Hum Mol Genet2024;33(20):1815–1832.
76.
PriyankaP, GopalakrishnanAP, NisarM, et al.A global phosphosite-correlated network map of Thousand And One Kinase 1 (TAOK1). Int J Biochem Cell Biol2024;170:106558.
77.
RaghuDH, DcunhaL, AhmedM, et al.Unravelling the phosphoregulatory network of protein kinase C-delta (PKC-delta). Biochim Biophys Acta Proteins Proteom2025;1873(5):141080.
78.
RameshP, NisarM, AmmankalluS, et al.Delineating protein biomarkers for gastric cancers: A catalogue of mass spectrometry-based markers and assessment of their suitability for targeted proteomics applications. J Proteomics2024;306:105262.
79.
RoukaE, SimisterPC, JanningM, et al.Differential recognition preferences of the three Src homology 3 (SH3) domains from the adaptor CD2-Associated Protein (CD2AP) and direct association with Ras and Rab Interactor 3 (RIN3). J Biol Chem2015;290(42):25275–25292.
80.
SahinI, KawanoY, Sklavenitis-PistofidisR, et al.Citron Rho-interacting kinase silencing causes cytokinesis failure and reduces tumor growth in multiple myeloma. Blood Adv2019;3(7):995–1002.
81.
SchifferM, MundelP, ShawAS, et al.A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis. J Biol Chem2004;279(35):37004–37012.
82.
SchwarzK, SimonsM, ReiserJ, et al.Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest2001;108(11):1621–1629.
83.
ShangN, WangJ, LiuZ, et al.Integrated analysis of disulfidptosis-related genes identifies CD2AP as a potential therapeutic target for hepatocellular carcinoma. Int J Mol Sci2025;26(9):4454.
84.
ShenJ, ZhaoY, ManY, et al.CLK3 promotes tumor proliferation by activating MYC signaling. Cell Div2024;19(1):28.
85.
ShihNY, LiJ, CotranR, et al.CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. Am J Pathol2001;159(6):2303–2308.
86.
SrivatsanS, SwieckiM, OteroK, et al.CD2-associated protein regulates plasmacytoid dendritic cell migration, but is dispensable for their development and cytokine production. J Immunol2013;191(12):5933–5940.
87.
SubramanianB, WilliamsS, KarpS, et al.INF2 mutations cause kidney disease through a gain-of-function mechanism. Sci Adv2024;10(46):eadr1017.
88.
SzaboMP, MishraS, KnuppA, et al.The role of Alzheimer’s disease risk genes in endolysosomal pathways. Neurobiol Dis2022;162:105576.
89.
TalbotK. Brain insulin resistance in Alzheimer’s disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag2014;4(1):31–40.
90.
TaoQQ, ChenYC, WuZY. The role of CD2AP in the pathogenesis of Alzheimer’s Disease. Aging Dis2019;10(4):901–907.
91.
TaoQQ, LiuZJ, SunYM, et al.Decreased gene expression of CD2AP in Chinese patients with sporadic Alzheimer’s disease. Neurobiol Aging2017;56:212 e215–212 e210.
92.
TossidouI, TengB, WorthmannK, et al.Tyrosine phosphorylation of CD2AP affects stability of the slit diaphragm complex. J Am Soc Nephrol2019;30(7):1220–1237.
93.
UbelmannF, BurrinhaT, SalavessaL, et al.Bin1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO Rep2017;18(1):102–122.
94.
Van AckerZP, BretouM, AnnaertW. Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: Impact of genetic risk factors. Mol Neurodegener2019;14(1):20.
95.
van DuijnTJ, AnthonyEC, HensbergenPJ, et al.Rac1 recruits the adapter protein CMS/CD2AP to cell-cell contacts. J Biol Chem2010;285(26):20137–20146.
96.
VandalM, JanmalekiM, ReaI, et al.CD2AP at the junction of nephropathy and Alzheimer’s disease. Mol Neurodegener2025;20(1):63.
97.
ViswanathanTM, ChitradeviK, ZochedhA, et al.Guanidine-Curcumin complex-loaded amine-functionalised hollow mesoporous silica nanoparticles for breast cancer therapy. Cancers (Basel)2022;14(14):3490.
98.
WolfG, StahlRA. CD2-associated protein and glomerular disease. Lancet2003;362(9397):1746–1748.
99.
WuY, WuM, WangZ, et al.PKG II secreted via the classical endoplasmic reticulum-Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect. Front Biosci (Landmark Ed)2022;27(2):53.
100.
XieW, ChenC, HanZ, et al.CD2AP inhibits metastasis in gastric cancer by promoting cellular adhesion and cytoskeleton assembly. Mol Carcinog2020;59(4):339–352.
101.
XuP, IanesC, GartnerF, et al.Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D). Gene2019;715:144005.
102.
XuT, ZhaoJ, XiongM. Graphical learning and causal inference for drug repurposing. medRxiv2023:2023.07.29.23293346; doi: 10.1101/2023.07.29.23293346
103.
YiY, LiP, HuangY, et al.P21-activated kinase 2-mediated beta-catenin signaling promotes cancer stemness and osimertinib resistance in EGFR-mutant non-small-cell lung cancer. Oncogene2022;41(37):4318–4329.
104.
YuanXZ, SunS, TanCC, et al.The role of ADAM10 in Alzheimer’s disease. J Alzheimers Dis2017;58(2):303–322.
105.
ZhangL, HeJ, ZhaoW, et al.CD2AP promotes the progression of glioblastoma multiforme via TRIM5-mediated NF-kB signaling. Cell Death Dis2024;15(10):722.
