title: Phosphatase of regenerating liver 3 (PRL3) provokes a tyrosine phosphoproteome to drive prometastatic signal transduction.
abstract: Phosphatase of regenerating liver 3 (PRL3) is suspected to be a causative factor toward cellular metastasis when in excess. To date, the molecular basis for PRL3 function remains an enigma, making efforts at distilling a concerted mechanism for PRL3-mediated metastatic dissemination very difficult. We previously discovered that PRL3 expressing cells exhibit a pronounced increase in protein tyrosine phosphorylation. Here we take an unbiased mass spectrometry-based approach toward identifying the phosphoproteins exhibiting enhanced levels of tyrosine phosphorylation with a goal to define the "PRL3-mediated signaling network." Phosphoproteomic data support intracellular activation of an extensive signaling network normally governed by extracellular ligand-activated transmembrane growth factor, cytokine, and integrin receptors in the PRL3 cells. Additionally, data implicate the Src tyrosine kinase as the major intracellular kinase responsible for "hijacking" this network and provide strong evidence that aberrant Src activation is a major consequence of PRL3 overexpression. Importantly, the data support a PDGF(α/β)-, Eph (A2/B3/B4)-, and Integrin (β1/β5)-receptor array as being the predominant network coordinator in the PRL3 cells, corroborating a PRL3-induced mesenchymal-state. Within this network, we find that tyrosine phosphorylation is increased on a multitude of signaling effectors responsible for Rho-family GTPase, PI3K-Akt, STAT, and ERK activation, linking observations made by the field as a whole under Src as a primary signal transducer. Our phosphoproteomic data paint the most comprehensive picture to date of how PRL3 drives prometastatic molecular events through Src activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202;
authors.forename: Chad D
authors.initials: CD
authors.lastname: Walls
authors.forename: Anton
authors.initials: A
authors.lastname: Iliuk
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Bai
authors.forename: Mu
authors.initials: M
authors.lastname: Wang
authors.forename: W Andy
authors.initials: WA
authors.lastname: Tao
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002999:Clone Cells; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism*; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016023:Integrins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D050791:STAT Transcription Factors; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D036081:Receptors, Eph Family; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; D020741:rho GTP-Binding Proteins
references.citation: Mol Cell Biol. 1988 Aug;8(8):3345-56
references.pmid: 2463476
references.citation: Cell. 2004 Jun 11;117(6):699-711
references.pmid: 15186772
references.citation: Oncogene. 1995 Apr 20;10(8):1475-83
references.pmid: 7537362
references.citation: J Biol Chem. 1996 Oct 18;271(42):25746-9
references.pmid: 8824201
references.citation: Nat Rev Cancer. 2010 Dec;10(12):858-70
references.pmid: 21102636
references.citation: Anticancer Agents Med Chem. 2011 Jan;11(1):99-108
references.pmid: 21291404
references.citation: Mol Cell Biol. 1994 Mar;14(3):1680-8
references.pmid: 7509446
references.citation: Cell Mol Life Sci. 2005 Sep;62(18):2092-9
references.pmid: 16132230
references.citation: Mol Cell Biol. 1996 Apr;16(4):1595-603
references.pmid: 8657134
references.citation: Mol Cell Biol. 1992 Dec;12(12):5843-56
references.pmid: 1448108
references.citation: Bioessays. 1998 Nov;20(11):913-21
references.pmid: 9872057
references.citation: Cancer Metastasis Rev. 2008 Jun;27(2):231-52
references.pmid: 18224294
references.citation: Biochem J. 2011 Apr 15;435(2):355-64
references.pmid: 21309750
references.citation: Cell. 1990 Aug 10;62(3):481-92
references.pmid: 1696179
references.citation: Exp Cell Res. 2000 Sep 15;259(2):370-7
references.pmid: 10964504
references.citation: FASEB J. 1995 Apr;9(7):484-96
references.pmid: 7737456
references.citation: Biochem Biophys Res Commun. 2013 Jan 4;430(1):196-201
references.pmid: 23178297
references.citation: J Biol Chem. 1997 Jan 31;272(5):2591-4
references.pmid: 9006890
references.citation: Annu Rev Cell Dev Biol. 2003;19:173-206
references.pmid: 14570568
references.citation: J Biol Chem. 2001 Jul 20;276(29):27455-61
references.pmid: 11337495
references.citation: Nature. 1993 May 27;363(6427):364-7
references.pmid: 8497321
references.citation: Science. 1997 Sep 12;277(5332):1630-5
references.pmid: 9287210
references.citation: Proteomics Clin Appl. 2007 Mar;1(3):246-63
references.pmid: 21136676
references.citation: Mol Cell Biol. 1996 Dec;16(12):6926-36
references.pmid: 8943348
references.citation: J Biol Chem. 1999 Sep 24;274(39):28050-7
references.pmid: 10488157
references.citation: Oncogene. 2000 Apr 20;19(17):2075-85
references.pmid: 10815799
references.citation: Anal Chem. 2009 May 1;81(9):3440-7
references.pmid: 19331382
references.citation: Proc Natl Acad Sci U S A. 1985 Dec;82(23):7845-9
references.pmid: 2415973
references.citation: Mol Cell. 2009 Nov 13;36(3):525-35
references.pmid: 19917259
references.citation: Cell. 2006 May 5;125(3):535-48
references.pmid: 16678097
references.citation: Cancer Cell. 2008 Jun;13(6):469-71
references.pmid: 18538730
references.citation: Mol Cell Biol. 1998 May;18(5):2553-8
references.pmid: 9566875
references.citation: Pathology. 2009 Feb;41(2):118-26
references.pmid: 19152186
references.citation: Oncogene. 2002 Mar 14;21(12):1870-5
references.pmid: 11896619
references.citation: Mol Cell Neurosci. 2013 Jan;52:106-16
references.pmid: 23147113
references.citation: Life Sci. 2010 Jan 2;86(1-2):66-72
references.pmid: 19945467
references.citation: Cancer Res. 2007 Apr 1;67(7):2922-6
references.pmid: 17409395
references.citation: Science. 1995 Jul 7;269(5220):81-3
references.pmid: 7541555
references.citation: Nat Rev Cancer. 2009 Nov;9(11):798-809
references.pmid: 19851315
references.citation: Trends Biochem Sci. 2003 Jun;28(6):284-93
references.pmid: 12826400
references.citation: Biochem J. 2004 May 15;380(Pt 1):1-17
references.pmid: 15040784
references.citation: EMBO J. 1993 Jun;12(6):2257-64
references.pmid: 7685273
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9796-801
references.pmid: 16777958
references.citation: Curr Biol. 1999 May 20;9(10):505-11
references.pmid: 10339427
references.citation: J Biol Chem. 2004 May 28;279(22):22893-901
references.pmid: 15044442
references.citation: Cell Signal. 2002 Sep;14(9):723-31
references.pmid: 12034353
references.citation: Am J Pathol. 2004 Jun;164(6):2039-54
references.pmid: 15161639
references.citation: Oncogene. 1998 Feb 19;16(7):891-901
references.pmid: 9484780
references.citation: Science. 2001 Nov 9;294(5545):1343-6
references.pmid: 11598267
references.citation: Biochem Biophys Res Commun. 2006 Mar 31;342(1):179-83
references.pmid: 16472776
references.citation: Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1272-6
references.pmid: 7877967
references.citation: Physiol Rev. 1999 Oct;79(4):1283-316
references.pmid: 10508235
references.citation: Mol Cell Proteomics. 2010 Oct;9(10):2162-72
references.pmid: 20562096
references.citation: Nat Rev Mol Cell Biol. 2002 Jul;3(7):475-86
references.pmid: 12094214
references.citation: Invest Ophthalmol Vis Sci. 2002 Feb;43(2):483-9
references.pmid: 11818394
references.citation: Mol Cell Biol. 1991 Jan;11(1):381-90
references.pmid: 1986233
references.citation: Oncogene. 2001 Oct 1;20(44):6403-17
references.pmid: 11607841
references.citation: Nat Cell Biol. 2004 Feb;6(2):154-61
references.pmid: 14743221
references.citation: Trends Biochem Sci. 2011 Feb;36(2):88-96
references.pmid: 20870410
references.citation: Exp Cell Res. 2000 Jun 15;257(2):245-54
references.pmid: 10837138
references.citation: Mol Cell Biol. 2000 Dec;20(23):9018-27
references.pmid: 11074000
references.citation: Science. 1994 Jun 3;264(5164):1415-21
references.pmid: 8197455
references.citation: Curr Opin Cell Biol. 2004 Feb;16(1):94-8
references.pmid: 15037311
references.citation: J Biol Chem. 1995 Oct 13;270(41):23934-6
references.pmid: 7592586
references.citation: Cancer Lett. 2006 Apr 8;235(1):1-10
references.pmid: 15907369
references.citation: Mol Cell. 2008 May 23;30(4):426-36
references.pmid: 18498747
references.citation: Mol Cell. 2008 May 9;30(3):303-14
references.pmid: 18471976
references.citation: Cell. 2002 Sep 20;110(6):673-87
references.pmid: 12297042
references.citation: Cancer Res. 2003 Jun 1;63(11):2716-22
references.pmid: 12782572
references.citation: J Biol Chem. 2008 Apr 18;283(16):10339-46
references.pmid: 18268019
references.citation: Curr Biol. 1997 Feb 1;7(2):85-94
references.pmid: 9024622
references.citation: Anal Biochem. 2004 Oct 1;333(1):174-81
references.pmid: 15351294
references.citation: Nature. 1993 Jan 28;361(6410):315-25
references.pmid: 8381210
references.citation: Nature. 1993 Jul 15;364(6434):249-52
references.pmid: 8321321
references.citation: Clin Cancer Res. 2004 Nov 1;10(21):7318-28
references.pmid: 15534108
references.citation: J Biol Chem. 2007 Feb 23;282(8):5413-9
references.pmid: 17192274
references.citation: Mol Cancer. 2009 Nov 24;8:110
references.pmid: 19930715
references.citation: Mol Cell Biol. 1994 Jun;14(6):3752-62
references.pmid: 8196618
references.citation: Oncogene. 1992 Nov;7(11):2259-62
references.pmid: 1437148
references.citation: Biochem Biophys Res Commun. 1997 Oct 20;239(2):493-7
references.pmid: 9344858
references.citation: Biochem Biophys Res Commun. 1998 Mar 17;244(2):421-7
references.pmid: 9514946
references.citation: J Biol Chem. 1996 Aug 30;271(35):20997-1000
references.pmid: 8798379
references.citation: J Biol Chem. 1995 Mar 31;270(13):7773-81
references.pmid: 7535778
references.citation: Oncogene. 2010 Mar 4;29(9):1303-15
references.pmid: 20010872
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 Jun;282(6):L1296-304
references.pmid: 12003786
references.citation: J Biol Chem. 2006 Apr 28;281(17):11972-80
references.pmid: 16507567
references.citation: Cancer Res. 2006 Mar 15;66(6):3153-61
references.pmid: 16540666
references.citation: Cancer Biol Ther. 2009 Jul;8(14):1352-9
references.pmid: 19440036
references.citation: J Biol Chem. 2008 Jun 6;283(23):16017-26
references.pmid: 18387945
references.citation: Biochem Soc Trans. 2004 Jun;32(Pt3):434-7
references.pmid: 15157154
references.citation: Cell Signal. 2009 Jul;21(7):1143-50
references.pmid: 19275932
references.citation: Annu Rev Immunol. 1998;16:293-322
references.pmid: 9597132
references.citation: Clin Cancer Res. 2003 Nov 15;9(15):5607-15
references.pmid: 14654542
references.citation: Cell. 1995 Jun 30;81(7):1147-57
references.pmid: 7600582
references.citation: Cell Signal. 2003 Feb;15(2):171-9
references.pmid: 12464388
references.citation: J Proteome Res. 2005 Jul-Aug;4(4):1442-50
references.pmid: 16083298
references.citation: Nat Neurosci. 2009 Mar;12(3):268-76
references.pmid: 19182796
references.citation: Trends Cell Biol. 2006 May;16(5):257-63
references.pmid: 16581250
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7319-24
references.pmid: 11404481
references.citation: J Cell Biochem. 2010 Dec 1;111(5):1087-98
references.pmid: 21053359
references.citation: Curr Opin Chem Biol. 2001 Aug;5(4):416-23
references.pmid: 11470605
references.citation: Mol Biol Cell. 1998 Dec;9(12):3367-82
references.pmid: 9843575
references.citation: Curr Biol. 1999 May 20;9(10):535-8
references.pmid: 10339428
references.citation: J Cell Sci. 2012 Aug 15;125(Pt 16):3883-92
references.pmid: 22595524
references.citation: Cancer Lett. 1996 Dec 20;110(1-2):49-55
references.pmid: 9018080
references.citation: Cell. 1996 Mar 8;84(5):723-34
references.pmid: 8625410