Acta Physiologica Sinica, August 25, 2012, 64(4): 489494

http://www.actaps.com.cn

489

Intersectin
12 11,*
3000602 271016

Intersectin/

Cdc42intersectin(Down syndrome, DS)(Alzheimer disease, AD)intersectin

intersectin
Q257

Function of intersectin in endocytosis and exocytosis

TIAN Chun-Ying1, ZHANG Chun-Ling2, GU Feng1, MA Yong-Jie1,*
Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China; 2College of Information Engineering, Taishan Medical University, Taian 271016, China

Abstract: Intersectin is an evolutionarily conserved multifunctional adaptor protein with multifunctional domains. These domains interact with components of the endocytic and exocytic pathways, such as the clathrin mediating synaptic vesicle recycling, the protein
related to endocytosis via caveolae, the with-no-lysine kinases related to the regulation of renal outer medullar potassium, and the
Cdc42 mediating exocytic pathway. Recently, the understanding of intersectin function in the pathogenesis of endocrine tumor and
many neurodegenerative diseases such as Down syndrome, Alzheimer disease has been deepened. This article reviewed the structure
and roles in endocytosis/exocytosis and diseases of intersectin.
Key words: intersectin; endocytosis; exocytosis; clathrin

intersectin

[1]

[2]Intersectin
/

1 Intersectin
1.1 Intersectin

intersectin intersectin1 intersectin2

[3] intersectin

[4]
in-

Received 2012-01-18 Accepted 2012-03-19

This review was supported by National Basic Research Development Program of China (No. 2006CB705600) and the National
Natural Science Foundation of China (No. 30700253, 30800355).
*
Corresponding author. Tel: +86-22-23340123-6134; E-mail: yongjiemagu@yahoo.com.cn

 Acta Physiologica Sinica, August 25, 2012, 64(4): 489494

490

tersectin (intersectin-L)
(intersectin-S) Intersectin-S
2 EH (Eps15 homology domain)1
[58]

5 SH3 (scr homology 3 domain)Intersectin-L

1 DH (Dbl homology
domain)1 PH (pleckstrin homology domain)

1 C2
Intersectin-S
[9,10]

intersectin-L Intersectin-S
intersectin-L
[6,1012]
1.2 Intersectin

SNARE (SNAP receptor)

v-SNARE
t-SNARE
(synaptobrevin)
v-SNARE syntaxin
t-SNARESNAP-25syntaxin synaptobrevin

intersectin1
SNAP-25
[23]
PC12 Intersectin1
SNAP-25 [24]Intersectin1

Intersectin

Intersectin-S intersectin-L
EH epsin1/2

intersectin1

stonedB[13,14]epsin1/2 [15]

[6]

stonedB
[14] Eps15

AP2

SNAP23/25 [16] 5

Pechstein [25] intersectin1 AP2 2

SH3 dynaminsyna-ptojaninWASP (Wiskott-Aldrich syndrome protein)Arp2/3 Sos

intersectin1AP2

[10, 13, 15, 17]Intersectin-L

DH Rho Cdc42

intersectin1AP2

(guanine nucleotide exchange factor,

GEF)[18] PH

Intersectin1-AP2 3

[19]PH DH
DH-PH DH

dynamin GTP

[20] C2

Evergren [18] intersec-

[21]

tin1 dynamin

2 Intersectin
2.1 Intersectin

intersectin1-dynamin

intersectin1 SH3 GST

Intersectin

intersectin1
dynamin intersectin1 SH3 AC

dynamin

(synaptic vesicle recycling)

intersectin1
intersectin2

[26]Pucharcos [4] intersectin2

intersectin2

[22]

491

Intersectin

WNK1 WNK4 PXXP

Pucharcos [4] intersectin1 in-

intersectin
II (pseud-

tersectin2

ohypoaldosteronism type2, PHA2)[30] WNK1

intersectin1 dynamin
intersectin2 SH3A (

WNK4 intersectin1 SH3

WNK

62%)
2.2 Intersectin

2.4 Intersectin

intersectin

intersectin SH3 dynamin

[15,27] intersectin1-S

Malacombe intersectin1-L
PC12

Cdc42
intersectin1-L

[27]

Yamabhai [15] intersectin
SH3 dynamin
SH3A dynamin
SH3C SH3E SH3B SH3D
dynamin Yoshida SH3
dynamin GTP
[28]

myc-SH3A
intersectin1 dy-

Knezevic

[29]

[24]
intersectin1
Malacombe DH
DH-PH DH-PH-C2
PC12
DH-PH DHPH-C2

namin2

DH [24]
Momboisse [33] DH-PH-C2

intersectin SH3A dynamin2

PC12
intersectin1-S

GTP dynamin2

DH-PH-C2 Cdc42 RNA

PC12 F-

SH3A

intersectin1-L Cdc42

2.3 Intersectin(with-no-lysine ki-

nases, WNK)

WNK1 WNK4
[30,31]WNK1
WNK4 intersectin

3 Intersectin
Intersectin1 21

WNK PXXP
PXXP intersectin

(Down syndrome, DS)

intersectin1

SH3 dynamin synaptojanin

[34] DS
35

(renal outer medullar potassium1, ROMK1)

[32]

intersectin1 WNK

[32]

(Alzheimer disease, AD)

Yu
intersectin1

 Acta Physiologica Sinica, August 25, 2012, 64(4): 489494

492

[6]

intersectin

[6]Inter-

[35]

sectin

[36]

Cdc42

inter-

(-PixN-WASP)
Cdc42 inter-

sectin1-L Cdc42

inter-

Cdc42
intersectin Cdc42 Ras
PC12

[37,38]

sectin1-S [44]
intersectin
sectin

[39,40]
intersectin EH
( EGFR)

Elk-1 [41]intersectin

Specht
intersectin2

11 Doherty GJ, McMahon HT. Mechanisms of endocytosis.

Annu Rev Biochem 2009; 78: 857902.
22 Momboisse F, Ory S, Ceridono M, Calco V, Vitale N, Bader
MF, Gasman S. The Rho guanine nucleotide exchange factors Intersectin 1L and beta-Pix control calcium-regulated
exocytosis in neuroendocrine PC12 cells. Cell Mol Neurobiol 2010; 30(8): 13271333.

5-

33 Tsyba L, Nikolaienko O, Dergai O, Dergai M, Novokhatska

[42]intersectin2

O, Skrypkina I, Rynditch A. Intersectin multidomain adaptor

proteins: Regulation of functional diversity. Gene 2011;

473(2): 6775.

44 Pucharcos C, Estivill X, de la Luna S. Intersectin 2, a new

Intersectin

[13,27,43]

Intersectin

intersectin
intersectin

multimodular protein involved in clathrin-mediated endocytosis. FEBS Lett 2000; 478(12): 4351.
55 Guipponi M, Scott HS, Chen H, Schebesta A, Rossier C, Antonarakis SE. Two isoforms of a human intersectin (ITSN)
protein are produced by brain-specific alternative splicing in
a stop codon. Genomics 1998; 53(3): 369376.
66 Yu Y, Chu PY, Bowser DN, Keating DJ, Dubach D, Harper I,
Tkalcevic J, Finkelstein DI, Pritchard MA. Mice deficient
for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities. Hum Mol Genet 2008; 17(21): 3281
3290.

77 Kropyvko S, Gerasymchuk D, Skrypkina I, Dergai M, Der-

Intersectin

gai O, Nikolaienko O, Rynditch A, Tsyba L. Structural diver-

intersectin
21
mRNA
[5]

intersectin
intersectin

sity and differential expression of novel human intersectin 1

isoforms. Mol Biol Rep 2010; 37(6): 27892796.
88 Blencowe BJ. Alternative splicing: new insights from global
analyses. Cell 2006; 126(1): 3747.
99 Roos J, Kelly RB. Dap160, a neural-specific Eps15 homology and multiple SH3 domain-containing protein that interacts with Drosophila dynamin. J Biol Chem 1998; 273(30):
1910819119.

493

Intersectin
111 Ma YJ, Okamoto M, Gu F, Obata K, Matsuyama T, Desaki J,

222 Okamoto M, Schoch S, Sudhof TC. EHSH1/intersectin, a

Tanaka J, Sakanaka M. Neuronal distribution of EHSH1/in-

protein that contains EH and SH3 domains and binds to dy-

tersectin: molecular linker between clathrin-mediated endo-

namin and SNAP-25. A protein connection between exocy-

cytosis and signaling pathways. J Neurosci Res 2003; 71(4):

tosis and endocytosis? J Biol Chem 1999; 274(26): 18446

468477.

18454.

111 Tsyba L, Skrypkina I, Rynditch A, Nikolaienko O, Ferenets

222 Malacombe M, Ceridono M, Calco V, Chasserot-Golaz S,

G, Fortna A, Gardiner K. Alternative splicing of mammalian

McPherson PS, Bader MF, Gasman S. Intersectin-1L nucle-

Intersectin 1: domain associations and tissue specificities.

otide exchange factor regulates secretory granule exocytosis

Genomics 2004; 84(1): 106113.

by activating Cdc42. EMBO J 2006; 25(15): 34943503.

111 Hussain NK, Yamabhai M, Ramjaun AR, Guy AM, Baranes

222 Pechstein A, Bacetic J, Vahedi-Faridi A, Gromova K, Sund-

D, O'Bryan JP, Der CJ, Kay BK, McPherson PS. Splice vari-

borger A, Tomlin N, Krainer G, Vorontsova O, Schafer JG,

ants of intersectin are components of the endocytic machin-

Owe SG, Cousin MA, Saenger W, Shupliakov O, Haucke V.

ery in neurons and nonneuronal cells. J Biol Chem 1999;

Regulation of synaptic vesicle recycling by complex forma-

274(22): 1567115677.

tion between intersectin 1 and the clathrin adaptor complex

111 Sengar AS, Wang W, Bishay J, Cohen S, Egan SE. The EH

AP2. Proc Natl Acad Sci U S A 2010; 107(9): 42064211.

and SH3 domain Ese proteins regulate endocytosis by link-

222 Klein IK, Predescu DN, Sharma T, Knezevic I, Malik AB,

ing to dynamin and Eps15. EMBO J 1999; 18(5): 1159

Predescu S. Intersectin-2L regulates caveola endocytosis

1171.

secondary to Cdc42-mediated actin polymerization. J Biol

111 Kelly LE, Phillips AM. Molecular and genetic characteriza-

Chem 2009; 284(38): 2595325961.

tion of the interactions between the Drosophila stoned-B

222 Predescu SA, Predescu DN, Timblin BK, Stan RV, Malik

protein and DAP-160 (intersectin). Biochem J 2005; 388(Pt

AB. Intersectin regulates fission and internalization of cave-

1): 195204.

olae in endothelial cells. Mol Biol Cell 2003; 14(12): 4997

111 Yamabhai M, Hoffman NG, Hardison NL, McPherson PS,

Castagnoli L, Cesareni G, Kay BK. Intersectin, a novel

5010.
222 Yoshida Y, Takei K. Stimulation of dynamin GTPase activity

adaptor protein with two Eps15 homology and five Src ho-

by amphiphysin. Methods Enzymol. 2005; 404: 528537.

mology 3 domains. J Biol Chem 1998; 273(47): 31401

222 Knezevic I, Predescu D, Bardita C, Wang M, Sharma T, Kei-

31407.

th B, Neamu R, Malik A, Predescu S. Regulation of dyna-

111 Keating DJ, Chen C, Pritchard MA. Alzheimers disease and

min-2 assembly-disassembly and function through the SH3A

endocytic dysfunction: clues from the Down syndrome-relat-

domain of intersectin-1s. J Cell Mol Med 2011; 15: 2364

ed proteins, DSCR1 and ITSN1. Ageing Res Rev 2006; 5(4):

2376

388401.

333 Huang CL, Yang SS, Lin SH. Mechanism of regulation of

111 Li SS. Specificity and versatility of SH3 and other prolinerecognition domains: structural basis and implications for
cellular signal transduction. Biochem J 2005; 390(Pt 3):
641653.

renal ion transport by WNK kinases. Curr Opin Nephrol

Hypertens 2008; 17(5): 519525.
333 Lazrak A, Liu Z, Huang CL. Antagonistic regulation of
ROMK by long and kidney-specific WNK1 isoforms. Proc

111 Evergren E, Gad H, Walther K, Sundborger A, Tomilin N,

Natl Acad Sci U S A 2006; 103(5): 16151620.

Shupliakov O. Intersectin is a negative regulator of dynamin

333 He G, Wang HR, Huang SK, Huang CL. Intersectin links

recruitment to the synaptic endocytic zone in the central syn-

WNK kinases to endocytosis of ROMK1. J Clin Invest 2007;

apse. J Neurosci 2007; 27(2): 379390.

111 Lemmon MA, Ferguson KM. Pleckstrin homology domains.
Curr Top Microbiol Immunol 1998; 228: 3974.
222 Rossman KL, Campbell SL. Bacterial expressed DH and
DH/PH domains. Methods Enzymol 2000; 325: 2538.
222 Rizo J, Sudhof TC. C2-domains, structure and function of a
universal Ca -binding domain. J Biol Chem 1998; 273(26):

117(4): 10781087.
333 Momboisse F, Ory S, Calco V, Malacombe M, Bader MF,
Gasman S. Calcium-regulated exocytosis in neuroendocrine
cells: intersectin-1L stimulates actin polymerization and exocytosis by activating Cdc42. Ann N Y Acad Sci 2009; 1152:
209214.

2+

333 Pucharcos C, Fuentes JJ, Casas C, de la Luna S, Alcantara S,

1587915882.

Arbones ML, Soriano E, Estivill X, Pritchard M. Alu-splice

222 Koh TW, Verstreken P, Bellen HJ. Dap160/intersectin acts as

cloning of human Intersectin (ITSN), a putative multivalent

a stabilizing scaffold required for synaptic development and

binding protein expressed in proliferating and differentiating

vesicle endocytosis. Neuron 2004; 43(2): 193205.

neurons and overexpressed in Down syndrome. Eur J Hum

 Acta Physiologica Sinica, August 25, 2012, 64(4): 489494

494
Genet 1999; 7(6): 704712.

444 Adams A, Thorn JM, Yamabhai M, Kay BK, OBryan JP. In-

333 Gratzl M, Breckner M, Prinz C. Mechanisms of storage and

tersectin, an adaptor protein involved in clathrin-mediated

exocytosis in neuroendocrine tumors. Endocr Pathol 2004;

endocytosis, activates mitogenic signaling pathways. J Biol

15(1): 116.

Chem 2000; 275(35): 2741427420.

333 Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet 2005; 366(9486): 665675.
333 Vega FM, Ridley AJ. Rho GTPases in cancer cell biology.
FEBS Lett 2008; 582(14): 20932101.
333 Ellenbroek SI, Collard JG. Rho GTPases: functions and association with cancer. Clin Exp Metastasis 2007; 24(8):
657672.

444 Specht K, Harbeck N, Smida J, Annecke K, Reich U, Naehrig J, Langer R, Mages J, Busch R, Kruse E, Klein-Hitpass
L, Schmitt M, Kiechle M, Hoefler H. Expression profiling
identifies genes that predict recurrence of breast cancer after
adjuvant CMF-based chemotherapy. Breast Cancer Res Treat
2009; 118(1): 4556.
444 Das M, Scappini E, Martin NP, Wong KA, Dunn S. Regula-

333 Wang JB, Wu WJ, Cerione RA. Cdc42 and Ras cooperate to

tion of neuron survival through an intersectin phosphoinosit-

mediate cellular transformation by intersectin-L. J Biol

ide 30-kinase C2b-AKT pathway. Mol Cell Biol 2007;

Chem 2005; 280(24): 2288322891.

27(22): 79067917.

444 Feng Q, Baird D, Yoo S, Antonyak M, Cerione RA. Phos-

444 Ma YJ, Wang B, Li W, Liu X, Wang J, Ding T, Zhang J, Ying

phorylation of the cool-1/beta-Pix protein serves as a regula-

G, Fu L, Gu F. Intersectin1-s is involved in migration and

tory signal for the migration and invasive activity of Src-

invasion of human glioma cells. J Neurosci Res 2011; 89(7):

transformed cells. J Biol Chem 2010; 285(24): 1880618816.

10791090.