1. Caveolin scaffolding domain
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First time, we termed “caveolin scaffolding domain” – in 1996.
Src Tyrosine Kinases, Gα Subunits, and H-Ras Share a
Common Membrane-anchored Scaffolding Protein,
Caveolin
CAVEOLIN BINDING NEGATIVELY REGULATES THE AUTO-
ACTIVATION OF Src TYROSINE KINASES*
1. Shengwen Li‡,
2. Jacques Couet§ and
3. Michael P. Lisanti¶
+ Author Affiliations
1. From the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142-1479
1. ¶To whom correspondence should be addressed. Tel.: 617-258-5225; Fax: 617-258-9872; E-mail:
lisanti@wi.mit.edu .
Abstract
Caveolae are plasma membrane specializations present in most cell types. Caveolin, a 22-kDa
integral membrane protein, is a principal structural and regulatory component of caveolae
membranes. Previous studies have demonstrated that caveolin co-purifies with lipid modified
signaling molecules, including Gα subunits, H-Ras, c-Src, and other related Src family tyrosine
kinases. In addition, it has been shown that caveolin interacts directly with Gα subunits and H-Ras,
preferentially recognizing the inactive conformation of these molecules. However, it is not known
whether caveolin interacts directly or indirectly with Src family tyrosine kinases. Here, we examine
the structural and functional interaction of caveolin with Src family tyrosine kinases. Caveolin was
2. recombinantly expressed as a glutathione S-transferase fusion. Using an established in vitro binding
assay, we find that caveolin interacts with wild-type Src (c-Src) but does not form a stable complex
with mutationally activated Src (v-Src). Thus, it appears that caveolin prefers the inactive
conformation of Src. Deletion mutagenesis indicates that the Src-interacting domain of caveolin is
located within residues 82-101, a cytosolic membrane-proximal region of caveolin. A caveolin
peptide derived from this region (residues 82-101) functionally suppressed the auto-activation of
purified recombinant c-Src tyrosine kinase and Fyn, a related Src family tyrosine kinase. We further
analyzed the effect of caveolin on c-Src activity in vivo by transiently co-expressing full-length
caveolin and c-Src tyrosine kinase in 293T cells. Co-expression with caveolin dramatically
suppressed the tyrosine kinase activity of c-Src as measured via an immune complex kinase assay.
Thus, it appears that caveolin structurally and functionally interacts with wild-type c-Src via caveolin
residues 82-101. Besides interacting with Src family kinases, this cytosolic caveolin domain (residues
82-101) has the following unique features. First, it is required to form multivalent homo-oligomers
of caveolin. Second, it interacts with G-protein α-subunits and down-regulates their GTPase activity.
Third, it binds to wild-type H-Ras. Fourth, it is membrane-proximal, suggesting that it may be
involved in other potential protein-protein interactions. Thus, we have termed this 20-amino
acid stretch of caveolin residues the caveolin scaffolding domain.
Reference:
doi: 10.1074/jbc.271.46.29182 November 15, 1996 The Journal of Biological
Chemistry 271, 29182-29190.
http://www.jbc.org/content/271/46/29182.short
PubMed search: Search results for “caveolin scaffolding domain”
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http://www.ncbi.nlm.nih.gov/pubmed/?term=caveolin+scaffolding+domain
~~~~
Tyrosine Kinases, Gα Subunits, and H-Ras Share a Common Membrane-
anchored Scaffolding Protein, Caveolin CAVEOLIN BINDING NEGATIVELY
REGULATES …
3. S Li, J Couet, MP Lisanti - Journal of Biological Chemistry, 1996 - ASBMB
... In this regard, several independent lines of evidence suggest that caveolin may function as a
scaffolding protein within caveolae ... Subsequently, these individual caveolin homo-oligomers
(4-6-nm particles) can interact with each other to form caveolae-like structures in vitro ...
Cited by 753Related articlesAll 10 versionsCiteSaved
Identification of peptide and protein ligands for the caveolin-scaffolding domain
Implications for the interaction of caveolin with caveolae-associated proteins
J Couet, S Li, T Okamoto, T Ikezu, MP Lisanti - Journal of Biological …, 1997 - ASBMB
Abstract Caveolin, a 21-24-kDa integral membrane protein, is a principal component of
caveolae membranes. We have suggested that caveolin functions as a scaffolding protein to
organize and concentrate certain caveolin-interacting proteins within caveolae ...
Cited by 851Related articlesAll 9 versionsCiteSavedMore
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Caveolin interaction with protein kinase c isoenzyme-dependent regulation of
kinase activity by the caveolin scaffolding domain peptide
N Oka, M Yamamoto, C Schwencke, J Kawabe… - Journal of Biological …, 1997 - ASBMB
Abstract Caveolar localization of protein kinase C and the regulation of caveolar function by
protein kinase C are well known. This study was undertaken to examine whether caveolin
subtypes interact with various protein kinase C isoenzymes using the caveolin scaffolding ...
Cited by 267Related articlesAll 6 versionsCiteSavedMore
[PDF] from researchgate.net
In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide
synthesis and reduces inflammation
M Bucci, JP Gratton, RD Rudic, L Acevedo… - Nature medicine, 2000 - nature.com
Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of
signal transduction through binding of its" scaffolding domain" to key signaling molecules.
However, the physiological importance of caveolin-1 in regulating signaling has been ...
Cited by 473Related articlesAll 7 versionsCiteSavedMore
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A role for the caveolin scaffolding domain in mediating the membrane
attachment of caveolin-1 The caveolin scaffolding domain is both necessary
and sufficient for …
A Schlegel, RB Schwab, PE Scherer… - Journal of Biological …, 1999 - ASBMB
4. Abstract Here, we have created a series of caveolin-1 (Cav-1) deletion mutants to examine
whether the membrane spanning segment is required for membrane attachment of caveolin-
1 in vivo. One mutant, Cav-1-(1–101), contains only the cytoplasmic N-terminal domain ...
Cited by 127Related articlesAll 6 versionsCiteSavedMore
[PDF] from nih.gov
A neutral sphingomyelinase resides in sphingolipid-enriched microdomains and
is inhibited by the caveolin-scaffolding domain: potential implications in tumour
…
RJ VELDMAN, N MAESTRE, OM ADUIB… - Biochemical …, 2001 - biochemj.org
Abstract Sphingomyelinases hydrolyse sphingomyelin to ceramide, a process involved in
signal-transduction routes leading to apoptosis and various other cellular responses. In the
present study, we investigated the sphingomyelinase content of caveolae, invaginated ...
Cited by 107Related articlesAll 4 versionsCiteSavedMore
Inhibition of PKCα and rhoA translocation in differentiated smooth muscle by a
caveolin scaffolding domain peptide
MJ Taggart, P Leavis, O Feron, KG Morgan - Experimental cell research, 2000 - Elsevier
Receptor-coupled contraction of smooth muscle involves recruitment to the plasma
membrane of downstream effector molecules PKCα and rhoA but the mechanism of this
signal integration is unclear. Caveolins, the principal structural proteins of caveolar ...
Cited by 77Related articlesAll 5 versionsCiteSavedMore
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Assembly of Trp1 in a signaling complex associated with caveolin-scaffolding
lipid raft domains
TP Lockwich, X Liu, BB Singh, J Jadlowiec… - Journal of Biological …, 2000 - ASBMB
Abstract Trp1 has been proposed as a component of the store-operated Ca 2+ entry (SOC)
channel. However, neither the molecular mechanism of SOC nor the role of Trp in this
process is yet understood. We have examined possible molecular interactions involved in ...
Cited by 356Related articlesAll 4 versionsCiteSavedMore
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Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle
Identification of a novel caveolin scaffolding/inhibitory domain
VJ Venema, H Ju, R Zou, RC Venema - Journal of Biological Chemistry, 1997 - ASBMB
Abstract Neuronal nitric-oxide synthase (nNOS) has been shown previously to interact with α
1-syntrophin in the dystrophin complex of skeletal muscle. In the present study, we have
examined whether nNOS also interacts with caveolin-3 in skeletal muscle. nNOS and ...
Cited by 239Related articlesAll 5 versionsCiteSaveSaved More
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5. [HTML] Caveolins, a family of scaffolding proteins for organizing “preassembled
signaling complexes” at the plasma membrane
T Okamoto, A Schlegel, PE Scherer… - Journal of Biological …, 1998 - ASBMB
... oligomers to interact with each other, thereby forming a caveolin-rich scaffold (14). ... and inactivation
of a diverse group of signaling molecules within caveolae membranes for ... Thus, the caveolin
scaffolding domain may function like other modular protein domains (Src homology-2 ...
Cited by 1543Related articlesAll 9 versionsCiteSaveSaved More
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The caveolin scaffolding domain modifies 2-amino-3-hydroxy-5-methyl-4-
isoxazole propionate receptor binding properties by inhibiting phospholipase A2
activity
SB Gaudreault, C Chabot, JP Gratton… - Journal of Biological …, 2004 - ASBMB
Abstract Activation of the enzyme phospholipase (PLA 2) has been proposed to be part of
the molecular mechanism involved in the alteration of 2-amino-3-hydroxy-5-methyl-4-
isoxazole propionate (AMPA) glutamate receptor responsiveness during long term ...
Cited by 62Related articlesAll 4 versionsCiteSaved
Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding
domain binding site interactions with and inhibition of serine/threonine protein …
L Li, CH Ren, SA Tahir, C Ren… - Molecular and cellular …, 2003 - Am Soc Microbiol
ABSTRACT Previously it has been reported that caveolin-1 (cav-1) has antiapoptotic
activities in prostate cancer cells and functions downstream of androgenic stimulation. In this
study, we demonstrate that cav-1 overexpression significantly reduced thapsigargin (Tg)- ...
Cited by 270Related articlesAll 7 versionsCiteSaveSaved More
[PDF] from donarmstrong.com
Caveolin scaffolding region and cholesterol-rich domains in membranes
RM Epand, BG Sayer, RF Epand - Journal of molecular biology, 2005 - Elsevier
A protein that constitutes a good marker for a type of cholesterol-rich domain in biological
membranes is caveolin. A segment of this protein has a sequence that corresponds to a
cholesterol recognition/interaction amino acid consensus (CRAC) motif; this motif has ...
Cited by 94Related articlesAll 9 versionsCiteSaveSaved More
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Dissecting the Interaction between Nitric Oxide Synthase (NOS) and Caveolin
FUNCTIONAL SIGNIFICANCE OF THE NOS CAVEOLIN BINDING DOMAININ
VIVO
6. G Garcı́a-Cardeña, P Martasek, BSS Masters… - Journal of Biological …, 1997 - ASBMB
... with both caveolin-1 and caveolin-3 and nNOS localizes in plasmalemmal domains of skeletal
muscle by virtue of its binding to dystrophin complexes (20), which are enriched in
caveolin-3-coated caveolae (21), we tested the ability of the scaffolding domain peptides derived ...
Cited by 741Related articlesAll 6 versionsCiteSavedMore
[HTML] from plos.org
[HTML] Evaluating caveolin interactions: do proteins interact with the caveolin
scaffolding domain through a widespread aromatic residue-rich motif?
DP Byrne, C Dart, DJ Rigden - PloS one, 2012 - journals.plos.org
Abstract Caveolins are coat proteins of caveolae, small flask-shaped pits of the plasma
membranes of most cells. Aside from roles in caveolae formation, caveolins recruit, retain
and regulate many caveolae-associated signalling molecules. Caveolin-protein ...
Cited by 35Related articlesAll 11 versionsCiteSaveSaved More
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… Tyrosine Kinases, Gα Subunits, and H-Ras Share a Common Membrane-
anchored Scaffolding Protein, Caveolin CAVEOLIN BINDING NEGATIVELY
REGULATES …
S Li, J Couet, MP Lisanti - Journal of Biological Chemistry, 1996 - ASBMB
... In this regard, several independent lines of evidence suggest that caveolin may function as a
scaffolding protein within caveolae ... Subsequently, these individual caveolin homo-oligomers
(4-6-nm particles) can interact with each other to form caveolae-like structures in vitro ...
Cited by 753Related articlesAll 10 versionsCiteSavedMore
Free from Publisher
[CITATION] Caveolin-1 regulates store-operated Ca2+ influx by binding of its
scaffolding domain to transient receptor potential channel-1 in endothelial cells
AM Kwiatek, RD Minshall, DR Cool, RA Skidgel… - Molecular …, 2006 - ASPET
Cited by 86Related articlesAll 6 versionsCiteSavedMore
[HTML] from physiology.org
[HTML] Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo
E Tourkina, M Richard, P Gööz… - American Journal of …, 2008 - Am Physiological Soc
7. Abstract Lung fibrosis involves the overexpression of ECM proteins, primarily collagen, by α-
smooth muscle actin (ASMA)-positive cells. Caveolin-1 is a master regulator of collagen
expression by cultured lung fibroblasts and of lung fibrosis in vivo. A peptide equivalent to ...
Cited by 94Related articlesAll 6 versionsCiteSaveSaved More
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Caveolin versus calmodulin counterbalancing allosteric modulators of
endothelial nitric oxide synthase
JB Michel, O Feron, K Sase, P Prabhakar… - Journal of Biological …, 1997 - ASBMB
... an oligomeric integral membrane protein that appears to serve as the structural “scaffold” within
caveolae. ... 7, 24) has led to the discovery of a direct interaction between caveolin and such ... α s .
These interactions appear to be mediated through a scaffolding domain comprising a ...
Cited by 342Related articlesAll 8 versionsCiteSaveSaved More
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Interaction of a receptor tyrosine kinase, EGF-R, with caveolins Caveolin binding
negatively regulates tyrosine and serine/threonine kinase activities
J Couet, M Sargiacomo, MP Lisanti - Journal of Biological Chemistry, 1997 - ASBMB
... direct interaction of caveolin with a growth factor receptor, EGF-R, a known caveolae-associated
receptor ... We now show that this caveolin binding motif within the kinase domain of the EGF-R
can mediate the interaction of the EGF-R with the scaffolding domains of caveolins ...
Cited by 589Related articlesAll 6 versionsCiteSaveSaved More
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[HTML] Role of the membrane interface on the conformation of the caveolin
scaffolding domain: a CD and NMR study
CL Lan, JM Neumann, N Jamin - FEBS letters, 2006 - Wiley Online Library
Abstract Circular dichroism (CD) and NMR spectroscopy were used to study the
conformational properties of two synthetic peptides, D82–R101 and D82–I109,
encompassing the caveolin scaffolding domain (D82–R101), in the presence of ...
Cited by 21Related articlesAll 7 versionsCiteSaveSaved