hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas.
The c-Met receptor tyrosine kinase (MetR) is frequently overexpressed and constitutively phosphorylated in a number of human malignancies. Activation of the receptor by its ligand, hepatocyte growth factor (HGF), leads to increased cell proliferation, motility, survival and disruption of adherens junctions. In this study, we show that hTid-1, a DNAJ/Hsp40 chaperone, represents a novel modulator of the MetR signaling pathway. hTid-1 is a co-chaperone of the Hsp70 family of proteins, and has been shown to regulate a number of cellular signaling proteins including several involved in tumorigenic and apoptotic pathways. In this study we demonstrate that hTid-1 binds to unphosphorylated MetR and becomes dissociated from the receptor upon HGF stimulation. Overexpression of the short form of hTid-1 (hTid-1(S)) in 786-0 renal clear cell carcinomas (RCCs) enhances MetR kinase activity leading to an increase in HGF-mediated cell migration with no discernible effect on cell proliferation. By contrast, knockdown of hTid-1 markedly impairs both the onset and amplitude of MetR phosphorylation in response to HGF without altering receptor protein levels. hTid-1-depleted cells display defective migratory properties, coincident with inhibition of ERK/MAP kinase and STAT3 pathways. Taken together, our findings denote hTid-1(S) as an essential regulatory component of MetR signaling. We propose that the binding of hTid-1(S) to MetR may stabilize the receptor in a ligand-competent state and this stabilizing function may influence conformational changes that take place during the catalytic cycle that promote kinase activation. Given the prevalence of HGF/MetR pathway activation in human cancers, targeted inhibition of hTid-1 may be a useful therapeutic in the management of MetR-dependent malignancies.
Department of Laboratory Medicine and Pathobiology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada.
E
E
Copeland
S
S
Balgobin
C M
CM
Lee
M
M
Rozakis-Adcock
D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D050956:HSP40 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction
C120664:DNAJA3 protein, human; D050956:HSP40 Heat-Shock Proteins; D019859:Proto-Oncogene Proteins c-met
J Biol Chem. 2001 Apr 20;276(16):13087-95
11116152
J Natl Cancer Inst. 2000 Oct 4;92(19):1564-72
11018092
Dev Genet. 1995;16(1):64-76
7758246
Oncogene. 2010 Feb 25;29(8):1155-66
19935715
Nature. 2007 Feb 15;445(7129):761-5
17230190
Cancer Cell. 2003 Apr;3(4):347-61
12726861
Oncogene. 2004 Nov 4;23(52):8419-31
15156195
FASEB J. 2005 Feb;19(2):267-9
15546961
Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
14685170
Oncogene. 2003 Jul 24;22(30):4636-41
12879007
Mol Cell Biol. 1999 Sep;19(9):5902-12
10454537
Cancer Res. 2004 Nov 1;64(21):7732-9
15520177
Exp Biol Med (Maywood). 2003 Feb;228(2):111-33
12563018
Cancer Res. 2006 Apr 1;66(7):3699-705
16585196
Int J Cancer. 1996 Jun 21;69(3):212-7
8682590
Neuron. 2008 Nov 26;60(4):625-41
19038220
Cell Cycle. 2007 Jun 1;6(11):1393-402
17525527
J Biol Chem. 1994 Feb 18;269(7):5446-51
8106526
J Biol Chem. 2008 Dec 5;283(49):34374-83
18819921
J Biol Chem. 1996 Jun 21;271(25):14840-8
8662861
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8499-504
10411904
Differentiation. 1992 Oct;51(2):91-104
1473626
Mol Cell Biol. 1997 Jan;17(1):318-25
8972212
J Pathol. 2009 Nov;219(3):347-55
19681071
Clin Cancer Res. 2002 Feb;8(2):620-7
11839685
Cancer Res. 2005 Apr 1;65(7):2520-5
15805242
Nature. 1996 Jun 13;381(6583):571-9
8637592
Anticancer Drugs. 2007 Nov;18(10):1173-81
17893518
Cell Signal. 2007 Sep;19(9):1973-85
17588722
Gene. 2001 Oct 31;278(1-2):201-10
11707338
Clin Cancer Res. 2004 Oct 1;10(19):6686-94
15475459
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595-9
8855223
Oncogene. 2001 May 17;20(22):2761-70
11420688
J Biol Chem. 2002 Jun 7;277(23):20605-10
11927590
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14531-6
16983094
Science. 1996 Dec 6;274(5293):1713-5
8939862
Cancer Res. 2000 Jan 15;60(2):342-9
10667586
Mol Cell Biol. 2005 Jan;25(1):44-59
15601829
FEBS Lett. 2004 Dec 17;578(3):323-30
15589840
Virology. 1998 Jul 20;247(1):74-85
9683573
Gastroenterology. 2010 Apr;138(4):1418-28
19900451
Nature. 1994 Jul 14;370(6485):111-7
8022479
Int J Mol Med. 2007 Oct;20(4):605-11
17786294
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4731-5
8197126
J Biol Chem. 2005 May 20;280(20):19461-71
15753086
Oncogene. 1995 Feb 16;10(4):739-49
7862451
Science. 1996 Dec 6;274(5293):1718-20
8939864
Cell Cycle. 2006 Dec;5(24):2839-41
17218789
J Biol Chem. 2001 Dec 28;276(52):49034-42
11679576
J Clin Invest. 1999 Dec;104(11):1583-91
10587522
J Cell Physiol. 2007 Nov;213(2):316-25
17607709