Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder refractory to current pharmacological therapies. Fibroblasts isolated from IPF patients display pathological activation of PI3K/Akt caused by low PTEN phosphatase activity. This enables these cells to escape the negative proliferative properties of polymerized collagen. The mechanism underlying low PTEN activity in IPF fibroblasts is unclear, but our prior studies indicate that membrane-associated PTEN expression is decreased in these cells. Caveolin-1 is an integral membrane protein whose expression is decreased in IPF lung tissue, but how low caveolin-1 contributes to pathological fibrosis is incompletely understood. The objective of this study was to examine the hypothesis that caveolin-1 regulates PTEN function in IPF fibroblasts. Here we demonstrate that caveolin-1 expression is a determinant of membrane PTEN levels and show that PTEN interacts with caveolin-1 via its caveolin-1-binding sequence. We demonstrate that caveolin-1 expression is low in IPF fibroblasts and that this correlates with low membrane PTEN levels, whereas overexpression of caveolin-1 restores membrane PTEN levels, inhibits Akt phosphorylation, and suppresses proliferation. We demonstrate that caveolin-1 and PTEN expression are low in myofibroblasts within IPF fibroblastic foci. These data indicate that IPF fibroblasts display low caveolin-1 expression, which results in low membrane-associated PTEN expression. This creates a membrane microenvironment depleted of inhibitory phosphatase activity, facilitating the aberrant activation PI3K/Akt and pathological proliferation.
Xia
Hong
H
Department of Medicine, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Khalil
Wajahat
W
Kahm
Judy
J
Jessurun
Jose
J
Kleidon
Jill
J
Henke
Craig A
CA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D051242:Caveolin 1; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
Am J Physiol Endocrinol Metab. 2003 Dec;285(6):E1151-60
14607781
Am J Pathol. 2009 Mar;174(3):746-61
19234134
J Exp Med. 2008 Jul 7;205(7):1659-72
18541712
J Biol Chem. 2001 Jan 12;276(2):993-8
11035045
J Biol Chem. 1999 Aug 6;274(32):22660-7
10428847
Thromb Haemost. 1999 Aug;82(2):291-7
10605716
Acta Histochem Cytochem. 2007 Jul 3;40(3):93-9
17653301
J Cell Sci. 2001 Jul;114(Pt 13):2375-82
11559746
Arthritis Rheum. 2008 Sep;58(9):2854-65
18759267
Cell. 1998 Oct 2;95(1):29-39
9778245
J Cell Sci. 2008 Jul 15;121(Pt 14):2360-71
18577581
Histochem Cell Biol. 2001 Apr;115(4):317-23
11405060
Biochem Biophys Res Commun. 2005 Dec 23;338(3):1383-90
16263077
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10182-7
10468583
J Biol Chem. 2003 Oct 10;278(41):40057-66
12869565
J Biol Chem. 1999 Jul 16;274(29):20693-703
10400703
Science. 2001 Sep 28;293(5539):2449-52
11498544
Cancer Res. 1997 Jun 1;57(11):2124-9
9187108
Mol Biol Cell. 2004 Feb;15(2):625-36
14657242
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13666-70
9391083
Am J Respir Crit Care Med. 2006 Jan 1;173(1):112-21
16179636
Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9407-11
7568142
Cell. 1996 Dec 13;87(6):1069-78
8978611
Cancer Biol Ther. 2008 Aug;7(8):1212-25
18458534
J Exp Med. 2006 Dec 25;203(13):2895-906
17178917
J Biol Chem. 1996 May 17;271(20):11930-5
8662667
Cell. 1999 Oct 29;99(3):323-34
10555148
Cancer Res. 2000 Jul 1;60(13):3605-11
10910075
J Cell Sci. 1980 Feb;41:159-75
7364880
Am J Pathol. 1991 May;138(5):1257-65
2024710
Am J Respir Crit Care Med. 2002 Jan 15;165(2):277-304
11790668
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4233-8
10760291
J Cell Physiol. 1988 Oct;137(1):185-91
3170657
Mol Cell Biol. 2000 Jul;20(14):5010-8
10866658
J Clin Invest. 1992 Nov;90(5):1778-85
1430204
J Biol Chem. 1997 Mar 7;272(10):6525-33
9045678
Mol Cell Biol. 2003 Dec;23(24):9389-404
14645548
Biochim Biophys Acta. 2009 Feb;1793(2):354-67
18992284