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FLASH GENE

Symbol

CD2AP

contributors: shn/mct - updated : 13-09-2016

HGNC name	CD2-associated protein
HGNC id	14258

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	FSGS3 focal segmental glomerulosclerosis 3
Location	6p12.3      Physical location : 47.445.524 - 47.594.994
Synonym name	cas ligand with multiple SH3 domains
	adapter protein CMS
	cas ligand with multiple Src homology 3 (SH3) domains
Synonym symbol(s)	CMS, DKFZP586H0519, FSGS3

DNA

TYPE	functioning gene
STRUCTURE	149.47 kb     18 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	region between -558 and -1bp ahead of the transcription start point is indispensable for the promoter activity of the human CD2AP gene
	A CREB site and two Sp1 sites were essential for maintaining the basal transcriptional activity of the human CD2AP promoter (not only CREB but also Sp1 plays a critical role in regulating basal CD2AP promoter activity in renal tubular epithelial cells)
	overexpression of E2F1 transactivates the CD2AP promoter ( E2F1 can bind to Sp1 binding site and overexpression of E2F1 is capable of increasing the binding of E2F1 and decreasing the binding of Sp1 to Sp1 binding sites)

MAPPING

cloned

Y

linked

N

status

provisional

Map	pter - D6S452 - D6S1651 - CD2AP - D6S1566 - D6S1669 - cen

RNA

TRANSCRIPTS	type	messenger

text	region between -558 and -1bp ahead of the transcription start point indispensable for the promoter activity of CD2AP gene CD2AP promoter contains an AP-1-like element

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_012120 18 - 5425 NP_036252 71.3 639 expressed in developing podocytes and widely in mature kidney 2000 10997929

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine     highly   liver         Endocrine pancreas         Lymphoid/Immune lymph node       highly Reproductive male system prostate       Urinary kidney nephron renal capsule glomerulus highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Urinary podocyte Homo sapiens

cell lineage	strongly expressed in glomerular podocytes
cell lines
fluid/secretion

at STAGE

physiological period

fetal

Text

pancreas

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	three SH3 domains in the NH2 terminus
	a coiled-coil domain
	proline-rich sequences in the center region

mono polymer

homomer , dimer

HOMOLOGY

interspecies	ortholog to Cd2ap, Mus musculus
	ortholog to Cd2ap, Rattus norvegicus
	ortholog to CD2AP, Pan troglodytes

Homologene

FAMILY

CATEGORY

adaptor , immunity/defense , storage

SUBCELLULAR LOCALIZATION	plasma membrane,junction
	intracellular
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,cytoskeleton
	intracellular,nucleus
text	cytoskeleton

basic FUNCTION	facilitate receptor patterning in the contact area by linking specific adhesion receptors to the cytoskeleton
	critical for stabilizing contacts between T cells and antigen-presenting cells
	scaffolding molecule that regulates the actin cytoskeleton
	promoting upregulation of actin stress fiber formation
	may anchor the podocyte slit diaphragm to the actin cytoskeleton in renal glomerulus
	acting as an adapter protein between membrane proteins and the actin cytoskeleton in interphase and during cytokinesis
	CD2AP-nephrin interactions are critical to maintaining slit diaphragm function and have a role in maintaining specialized subcellular architecture
	has a role in polycystin-2 function
	might be a downstream mediator of EGF/EGFR signaling transduction pathway
	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
	required for early activation of anti-apoptotic phosphatidylinositol 3-kinase (PI3K)/AKT and has a role in maintaining podocyte survival
	involved in several molecular signaling pathways and is an important factor responsible for nephrotic syndrome
	scaffold adaptor protein that associates with cortactin, a protein also involved in the regulation of receptor-mediated endocytosis
	adaptor protein that plays a role in endocytosis, cell motility, and cell survival
	plays a critical role in the maintenance of the kidney filtration barrier
	adaptor molecule involved in the internalization of ubiquitinated RTKs, and associated with RET under basal, unstimulated conditions in neurons
	CD2AP and CBLC, constitute a checkpoint that controls the extent of RET downregulation and, thereby, the sensitivity of neurons to glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs)
	is a crucial protein for the slit-diaphragm assembly and function
	participates in antiapoptotic regulation in the human renal tubular epithelial cells. Antiapoptotic effect of EGF/CD2AP signal transduction is mediated by JunD and c-fos
	scaffolding protein interacting with the nephrin-receptor complex, which is considered to play an important role in the maintenance of the slit diaphragm
	may play a crucial role in albumin overload-induced ER stress and apoptosis in podocytes
	adaptor molecule involved in T cell receptor signaling and podocyte homeostasis
	major function of CD2AP is likely on the actin cytoskeleton, affecting migration to local lymph nodes under conditions of inflammation
	actin barbed-end capping protein responsible for actin stability at the adherens junction
	multidomain scaffolding protein that has a critical role in renal function
	in podocytes serves as an adaptor protein binding to nephrin and podocin, anchoring these slit diaphragm proteins to actin filaments of podocyte cytoskeleton, and sending signals inward or outward
	role in podocyte apoptosis and proteinuria induced by angiotensin II

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

immunity/defense

PATHWAY

metabolism

signaling

signal transduction

	potential signaling pathway between PAX2 and CD2AP in the renal interstitial fibrosis disease
	Golgi-traversing pathway for exosomal release of the cargo protein GPRC5B in which CD2AP facilitates the entry and LMAN2 impedes the exit of the flux, respectively

a component	component of the slit membrane of the glomerular podocytes
	SH3BP1 formed a complex with CGNL1/paracingulin, a junctional adaptor, and CD2AP, a scaffolding protein, and both were required for normal CDC42 signaling and junction formation

INTERACTION

DNA

RNA	a critical role CREB and Sp1 in regulating basal CD2AP promoter activity in renal tubular epithelial cells
	EGF activates the human CD2AP promoter in renal tubular epithelial cells
	EGF-induced JunD/c-fos complexes bind to the human CD2AP gene promoter via an P-1-Like element in human renal tubular epithelial cells

small molecule

protein	cytoplasmic domain of CD2 molecule
	proto-oncogenic protein c-Cbl (SH3KBP1)
	RAB4A, member RAS oncogene family (RAB4A)
	focal adhesion protein p130(Cas)
	family with sequence similarity 125, member A (olso known as CFBP)
	polycystic kidney disease 2 (PKD2)
	vinculin
	cortactin binding
	PSTPIP1, ARHGAP27, CAPZA1
	anillin, a specific cleavage furrow component
	cytoplasmic domain of nephrosis 1, congenital, Finnish type (nephrin, NPHS1) and nephrosis 2, idiopathic, steroid-resistant (podocin, NPHS2) in podocytes
	functional competition of CD2AP and SH3KBP1 for binding to nephrin and podocin (when both proteins are coexpressed, nephrin and podocin bind preferentially to CD2AP)
	INPPL1 interacts with CD2AP in glomeruli and is expressed in podocytes, where it translocates to plasma membrane after insulin stimulation
	transcription factor SP1 and SP3 up-regulate the basal transcriptional activity of CD2AP and increase CD2AP expression at mRNA level
	SEPT7 associates with CD2AP and NPHS1, both essential for glomerular ultrafiltration
	efficient colocalization of capping protein (CP) and CTTN at the cell periphery required CD2AP
	adaptor protein CD2AP-mediated internalization following cell surface delivery appears to contribute to the Golgi accumulation of GPRC5B, possibly in parallel with biosynthetic/secretory trafficking from the endoplasmic reticulum

cell & other

REGULATION

activated by

epidermal growth factor (EGF) in renal tubular epithelial cells

ASSOCIATED DISORDERS

corresponding disease(s)

FSGS3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in Congenital nephrotic syndrome of the Finnish type (CNF) constitutional     --low   in diabetic conditions in podocytes via PI3-K/Akt signaling

Susceptibility

to glomerulosclerosis and glomerular disease to Alzheimer disease toend-stage renal disease (ESRD) in patients with type 1 diabetes

Variant & Polymorphism SNP	strongly associated with Alzheimer disease
	CD2AP gene variants may contribute to susceptibility to ESRD in patients with type 1 diabetes

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	CD2AP-deficient mice die at 6 to 7 weeks of age from renal failure. Knockout mice exhibited exhibited nephrotic syndrome and renal failure: defects in epithelial cell foot processes, mesangial cell hyperplasia and extracellular matrix deposition
	Mice lacking CD2AP exhibit a congenital nephrotic syndrome characterized by extensive foot process effacement
	Mice lacking CD2AP die at 6 weeks of age. Mice with CD2AP haploinsufficiency developed glomerular changes at 9 months and had increased susceptibility to glomerular injury by nephrotoxic antibodies or immune complexes