Abstract
The Drosophila PS1 and PS2 integrins are required to maintain the connection between the dorsal and ventral wing epithelia. If alphaPS subunits are inappropriately expressed during early pupariation, the epithelia separate, causing a wing blister. Two lines of evidence indicate that this apparent loss-of-function phenotype is not a dominant negative effect, but is due to inappropriate expression of functional integrins: wing blisters are not generated efficiently by misexpression of loss-of-function alphaPS2 subunits with mutations that inhibit ligand binding, and gain-of-function, hyperactivated mutant alphaPS2 proteins cause blistering at expression levels well below those required by wild-type proteins. A genetic screen for dominant suppressors of wing blisters generated null alleles of a gene named moleskin, which encodes the protein DIM-7. DIM-7, a Drosophila homolog of vertebrate importin-7, has recently been shown to bind the SHP-2 tyrosine phosphatase homolog Corkscrew and to be important in the nuclear translocation of activated D-ERK. Consistent with this latter finding, homozygous mutant clones of moleskin fail to grow in the wing. Genetic tests suggest that the moleskin suppression of wing blisters is not directly related to inhibition of D-ERK nuclear import. These data are discussed with respect to the possible regulation of integrin function by cytoplasmic ERK.
Full Text
The Full Text of this article is available as a PDF (268.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allard J. D., Chang H. C., Herbst R., McNeill H., Simon M. A. The SH2-containing tyrosine phosphatase corkscrew is required during signaling by sevenless, Ras1 and Raf. Development. 1996 Apr;122(4):1137–1146. doi: 10.1242/dev.122.4.1137. [DOI] [PubMed] [Google Scholar]
- Allard J. D., Herbst R., Carroll P. M., Simon M. A. Mutational analysis of the SRC homology 2 domain protein-tyrosine phosphatase Corkscrew. J Biol Chem. 1998 May 22;273(21):13129–13135. doi: 10.1074/jbc.273.21.13129. [DOI] [PubMed] [Google Scholar]
- Aplin A. E., Stewart S. A., Assoian R. K., Juliano R. L. Integrin-mediated adhesion regulates ERK nuclear translocation and phosphorylation of Elk-1. J Cell Biol. 2001 Apr 16;153(2):273–282. doi: 10.1083/jcb.153.2.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baker N. E., Rubin G. M. Effect on eye development of dominant mutations in Drosophila homologue of the EGF receptor. Nature. 1989 Jul 13;340(6229):150–153. doi: 10.1038/340150a0. [DOI] [PubMed] [Google Scholar]
- Bianchi E., Denti S., Granata A., Bossi G., Geginat J., Villa A., Rogge L., Pardi R. Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity. Nature. 2000 Apr 6;404(6778):617–621. doi: 10.1038/35007098. [DOI] [PubMed] [Google Scholar]
- Brabant M. C., Fristrom D., Bunch T. A., Baker S. E., Brower D. L. The PS integrins are required for a regulatory event during Drosophila wing morphogenesis. Ann N Y Acad Sci. 1998 Oct 23;857:99–109. doi: 10.1111/j.1749-6632.1998.tb10110.x. [DOI] [PubMed] [Google Scholar]
- Brand A. H., Manoukian A. S., Perrimon N. Ectopic expression in Drosophila. Methods Cell Biol. 1994;44:635–654. doi: 10.1016/s0091-679x(08)60936-x. [DOI] [PubMed] [Google Scholar]
- Brower D. L., Bunch T. A., Mukai L., Adamson T. E., Wehrli M., Lam S., Friedlander E., Roote C. E., Zusman S. Nonequivalent requirements for PS1 and PS2 integrin at cell attachments in Drosophila: genetic analysis of the alpha PS1 integrin subunit. Development. 1995 May;121(5):1311–1320. doi: 10.1242/dev.121.5.1311. [DOI] [PubMed] [Google Scholar]
- Brower D. L., Piovant M., Reger L. A. Developmental analysis of Drosophila position-specific antigens. Dev Biol. 1985 Mar;108(1):120–130. doi: 10.1016/0012-1606(85)90014-4. [DOI] [PubMed] [Google Scholar]
- Brown N. H., Gregory S. L., Martin-Bermudo M. D. Integrins as mediators of morphogenesis in Drosophila. Dev Biol. 2000 Jul 1;223(1):1–16. doi: 10.1006/dbio.2000.9711. [DOI] [PubMed] [Google Scholar]
- Brown N. H., King D. L., Wilcox M., Kafatos F. C. Developmentally regulated alternative splicing of Drosophila integrin PS2 alpha transcripts. Cell. 1989 Oct 6;59(1):185–195. doi: 10.1016/0092-8674(89)90880-5. [DOI] [PubMed] [Google Scholar]
- Brunner D., Oellers N., Szabad J., Biggs W. H., 3rd, Zipursky S. L., Hafen E. A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways. Cell. 1994 Mar 11;76(5):875–888. doi: 10.1016/0092-8674(94)90362-x. [DOI] [PubMed] [Google Scholar]
- Bunch T. A., Brower D. L. Drosophila PS2 integrin mediates RGD-dependent cell-matrix interactions. Development. 1992 Sep;116(1):239–247. doi: 10.1242/dev.116.1.239. [DOI] [PubMed] [Google Scholar]
- Catella-Lawson F., Kapoor S., Moretti D., De Marco S., Vigilante G. J., Cucchiara A. J., Ramsey K. E., Combe S., Rocca B., Theroux P. Oral glycoprotein IIb/IIIa antagonism in patients with coronary artery disease. Am J Cardiol. 2001 Aug 1;88(3):236–242. doi: 10.1016/s0002-9149(01)01632-0. [DOI] [PubMed] [Google Scholar]
- Cleghon V., Feldmann P., Ghiglione C., Copeland T. D., Perrimon N., Hughes D. A., Morrison D. K. Opposing actions of CSW and RasGAP modulate the strength of Torso RTK signaling in the Drosophila terminal pathway. Mol Cell. 1998 Dec;2(6):719–727. doi: 10.1016/s1097-2765(00)80287-7. [DOI] [PubMed] [Google Scholar]
- Condie J. M., Brower D. L. Allelic interactions at the engrailed locus of Drosophila: engrailed protein expression in imaginal discs. Dev Biol. 1989 Sep;135(1):31–42. doi: 10.1016/0012-1606(89)90155-3. [DOI] [PubMed] [Google Scholar]
- DeMali K. A., Balciunaite E., Kazlauskas A. Integrins enhance platelet-derived growth factor (PDGF)-dependent responses by altering the signal relay enzymes that are recruited to the PDGF beta receptor. J Biol Chem. 1999 Jul 9;274(28):19551–19558. doi: 10.1074/jbc.274.28.19551. [DOI] [PubMed] [Google Scholar]
- Dedhar S., Hannigan G. E. Integrin cytoplasmic interactions and bidirectional transmembrane signalling. Curr Opin Cell Biol. 1996 Oct;8(5):657–669. doi: 10.1016/s0955-0674(96)80107-4. [DOI] [PubMed] [Google Scholar]
- Diaz-Benjumea F. J., Hafen E. The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development. Development. 1994 Mar;120(3):569–578. doi: 10.1242/dev.120.3.569. [DOI] [PubMed] [Google Scholar]
- Díaz-Benjumea F. J., García-Bellido A. Behaviour of cells mutant for an EGF receptor homologue of Drosophila in genetic mosaics. Proc Biol Sci. 1990 Oct 22;242(1303):36–44. doi: 10.1098/rspb.1990.0100. [DOI] [PubMed] [Google Scholar]
- Feng G. S. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp Cell Res. 1999 Nov 25;253(1):47–54. doi: 10.1006/excr.1999.4668. [DOI] [PubMed] [Google Scholar]
- Fernandez C., Clark K., Burrows L., Schofield N. R., Humphries M. J. Regulation of the extracellular ligand binding activity of integrins. Front Biosci. 1998 Jul 2;3:d684–d700. doi: 10.2741/a313. [DOI] [PubMed] [Google Scholar]
- Giancotti F. G., Ruoslahti E. Integrin signaling. Science. 1999 Aug 13;285(5430):1028–1032. doi: 10.1126/science.285.5430.1028. [DOI] [PubMed] [Google Scholar]
- Gotwals P. J., Paine-Saunders S. E., Stark K. A., Hynes R. O. Drosophila integrins and their ligands. Curr Opin Cell Biol. 1994 Oct;6(5):734–739. doi: 10.1016/0955-0674(94)90101-5. [DOI] [PubMed] [Google Scholar]
- Grotewiel M. S., Beck C. D., Wu K. H., Zhu X. R., Davis R. L. Integrin-mediated short-term memory in Drosophila. Nature. 1998 Jan 29;391(6666):455–460. doi: 10.1038/35079. [DOI] [PubMed] [Google Scholar]
- Gruss O. J., Carazo-Salas R. E., Schatz C. A., Guarguaglini G., Kast J., Wilm M., Le Bot N., Vernos I., Karsenti E., Mattaj I. W. Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity. Cell. 2001 Jan 12;104(1):83–93. doi: 10.1016/s0092-8674(01)00193-3. [DOI] [PubMed] [Google Scholar]
- Guichard A., Biehs B., Sturtevant M. A., Wickline L., Chacko J., Howard K., Bier E. rhomboid and Star interact synergistically to promote EGFR/MAPK signaling during Drosophila wing vein development. Development. 1999 Jun;126(12):2663–2676. doi: 10.1242/dev.126.12.2663. [DOI] [PubMed] [Google Scholar]
- Görlich D., Kutay U. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol. 1999;15:607–660. doi: 10.1146/annurev.cellbio.15.1.607. [DOI] [PubMed] [Google Scholar]
- Herbst R., Carroll P. M., Allard J. D., Schilling J., Raabe T., Simon M. A. Daughter of sevenless is a substrate of the phosphotyrosine phosphatase Corkscrew and functions during sevenless signaling. Cell. 1996 Jun 14;85(6):899–909. doi: 10.1016/s0092-8674(00)81273-8. [DOI] [PubMed] [Google Scholar]
- Hirsch Emilio, Barberis Laura, Brancaccio Mara, Azzolino Ornella, Xu Dazhong, Kyriakis John M., Silengo Lorenzo, Giancotti Filippo G., Tarone Guido, Fässler Reinhard. Defective Rac-mediated proliferation and survival after targeted mutation of the beta1 integrin cytodomain. J Cell Biol. 2002 Apr 29;157(3):481–492. doi: 10.1083/jcb.200111065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Howe A., Aplin A. E., Alahari S. K., Juliano R. L. Integrin signaling and cell growth control. Curr Opin Cell Biol. 1998 Apr;10(2):220–231. doi: 10.1016/s0955-0674(98)80144-0. [DOI] [PubMed] [Google Scholar]
- Hughes P. E., Pfaff M. Integrin affinity modulation. Trends Cell Biol. 1998 Sep;8(9):359–364. doi: 10.1016/s0962-8924(98)01339-7. [DOI] [PubMed] [Google Scholar]
- Hughes P. E., Renshaw M. W., Pfaff M., Forsyth J., Keivens V. M., Schwartz M. A., Ginsberg M. H. Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway. Cell. 1997 Feb 21;88(4):521–530. doi: 10.1016/s0092-8674(00)81892-9. [DOI] [PubMed] [Google Scholar]
- Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
- Inagaki K., Yamao T., Noguchi T., Matozaki T., Fukunaga K., Takada T., Hosooka T., Akira S., Kasuga M. SHPS-1 regulates integrin-mediated cytoskeletal reorganization and cell motility. EMBO J. 2000 Dec 15;19(24):6721–6731. doi: 10.1093/emboj/19.24.6721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Irie A., Kamata T., Puzon-McLaughlin W., Takada Y. Critical amino acid residues for ligand binding are clustered in a predicted beta-turn of the third N-terminal repeat in the integrin alpha 4 and alpha 5 subunits. EMBO J. 1995 Nov 15;14(22):5550–5556. doi: 10.1002/j.1460-2075.1995.tb00242.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jackson D. E., Ward C. M., Wang R., Newman P. J. The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling. J Biol Chem. 1997 Mar 14;272(11):6986–6993. doi: 10.1074/jbc.272.11.6986. [DOI] [PubMed] [Google Scholar]
- Jannuzi Alison L., Bunch Thomas A., Brabant Marc C., Miller Steven W., Mukai Leona, Zavortink Michael, Brower Danny L. Disruption of C-terminal cytoplasmic domain of betaPS integrin subunit has dominant negative properties in developing Drosophila. Mol Biol Cell. 2002 Apr;13(4):1352–1365. doi: 10.1091/mbc.01-08-0429. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson Hamlet M. R., Perkins L. A. Analysis of corkscrew signaling in the Drosophila epidermal growth factor receptor pathway during myogenesis. Genetics. 2001 Nov;159(3):1073–1087. doi: 10.1093/genetics/159.3.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jäkel S., Albig W., Kutay U., Bischoff F. R., Schwamborn K., Doenecke D., Görlich D. The importin beta/importin 7 heterodimer is a functional nuclear import receptor for histone H1. EMBO J. 1999 May 4;18(9):2411–2423. doi: 10.1093/emboj/18.9.2411. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lacalle Rosa Ana, Mira Emilia, Gomez-Mouton Concepcion, Jimenez-Baranda Sonia, Martinez-A Carlos, Manes Santos. Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation. J Cell Biol. 2002 Apr 15;157(2):277–289. doi: 10.1083/jcb.200109031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lorenzen J. A., Baker S. E., Denhez F., Melnick M. B., Brower D. L., Perkins L. A. Nuclear import of activated D-ERK by DIM-7, an importin family member encoded by the gene moleskin. Development. 2001 Apr;128(8):1403–1414. doi: 10.1242/dev.128.8.1403. [DOI] [PubMed] [Google Scholar]
- MacKrell A. J., Blumberg B., Haynes S. R., Fessler J. H. The lethal myospheroid gene of Drosophila encodes a membrane protein homologous to vertebrate integrin beta subunits. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2633–2637. doi: 10.1073/pnas.85.8.2633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manseau L., Baradaran A., Brower D., Budhu A., Elefant F., Phan H., Philp A. V., Yang M., Glover D., Kaiser K. GAL4 enhancer traps expressed in the embryo, larval brain, imaginal discs, and ovary of Drosophila. Dev Dyn. 1997 Jul;209(3):310–322. doi: 10.1002/(SICI)1097-0177(199707)209:3<310::AID-AJA6>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
- Martin-Bermudo M. D., Dunin-Borkowski O. M., Brown N. H. Modulation of integrin activity is vital for morphogenesis. J Cell Biol. 1998 May 18;141(4):1073–1081. doi: 10.1083/jcb.141.4.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martín-Blanco E., Roch F., Noll E., Baonza A., Duffy J. B., Perrimon N. A temporal switch in DER signaling controls the specification and differentiation of veins and interveins in the Drosophila wing. Development. 1999 Dec;126(24):5739–5747. doi: 10.1242/dev.126.24.5739. [DOI] [PubMed] [Google Scholar]
- Mañes S., Mira E., Gómez-Mouton C., Zhao Z. J., Lacalle R. A., Martínez-A C. Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. Mol Cell Biol. 1999 Apr;19(4):3125–3135. doi: 10.1128/mcb.19.4.3125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nachury M. V., Maresca T. J., Salmon W. C., Waterman-Storer C. M., Heald R., Weis K. Importin beta is a mitotic target of the small GTPase Ran in spindle assembly. Cell. 2001 Jan 12;104(1):95–106. doi: 10.1016/s0092-8674(01)00194-5. [DOI] [PubMed] [Google Scholar]
- O'Toole T. E., Katagiri Y., Faull R. J., Peter K., Tamura R., Quaranta V., Loftus J. C., Shattil S. J., Ginsberg M. H. Integrin cytoplasmic domains mediate inside-out signal transduction. J Cell Biol. 1994 Mar;124(6):1047–1059. doi: 10.1083/jcb.124.6.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oh E. S., Gu H., Saxton T. M., Timms J. F., Hausdorff S., Frevert E. U., Kahn B. B., Pawson T., Neel B. G., Thomas S. M. Regulation of early events in integrin signaling by protein tyrosine phosphatase SHP-2. Mol Cell Biol. 1999 Apr;19(4):3205–3215. doi: 10.1128/mcb.19.4.3205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Perkins L. A., Johnson M. R., Melnick M. B., Perrimon N. The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila. Dev Biol. 1996 Nov 25;180(1):63–81. doi: 10.1006/dbio.1996.0285. [DOI] [PubMed] [Google Scholar]
- Sagawa K., Kimura T., Swieter M., Siraganian R. P. The protein-tyrosine phosphatase SHP-2 associates with tyrosine-phosphorylated adhesion molecule PECAM-1 (CD31). J Biol Chem. 1997 Dec 5;272(49):31086–31091. doi: 10.1074/jbc.272.49.31086. [DOI] [PubMed] [Google Scholar]
- Schoenwaelder S. M., Petch L. A., Williamson D., Shen R., Feng G. S., Burridge K. The protein tyrosine phosphatase Shp-2 regulates RhoA activity. Curr Biol. 2000 Nov 30;10(23):1523–1526. doi: 10.1016/s0960-9822(00)00831-9. [DOI] [PubMed] [Google Scholar]
- Stark K. A., Yee G. H., Roote C. E., Williams E. L., Zusman S., Hynes R. O. A novel alpha integrin subunit associates with betaPS and functions in tissue morphogenesis and movement during Drosophila development. Development. 1997 Nov;124(22):4583–4594. doi: 10.1242/dev.124.22.4583. [DOI] [PubMed] [Google Scholar]
- Struhl G., Basler K. Organizing activity of wingless protein in Drosophila. Cell. 1993 Feb 26;72(4):527–540. doi: 10.1016/0092-8674(93)90072-x. [DOI] [PubMed] [Google Scholar]
- Tanoue T., Adachi M., Moriguchi T., Nishida E. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol. 2000 Feb;2(2):110–116. doi: 10.1038/35000065. [DOI] [PubMed] [Google Scholar]
- Tsuda M., Matozaki T., Fukunaga K., Fujioka Y., Imamoto A., Noguchi T., Takada T., Yamao T., Takeda H., Ochi F. Integrin-mediated tyrosine phosphorylation of SHPS-1 and its association with SHP-2. Roles of Fak and Src family kinases. J Biol Chem. 1998 May 22;273(21):13223–13229. doi: 10.1074/jbc.273.21.13223. [DOI] [PubMed] [Google Scholar]
- Walsh E. P., Brown N. H. A screen to identify Drosophila genes required for integrin-mediated adhesion. Genetics. 1998 Oct;150(2):791–805. doi: 10.1093/genetics/150.2.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wehrli M., DiAntonio A., Fearnley I. M., Smith R. J., Wilcox M. Cloning and characterization of alpha PS1, a novel Drosophila melanogaster integrin. Mech Dev. 1993 Sep;43(1):21–36. doi: 10.1016/0925-4773(93)90020-x. [DOI] [PubMed] [Google Scholar]
- Wiese C., Wilde A., Moore M. S., Adam S. A., Merdes A., Zheng Y. Role of importin-beta in coupling Ran to downstream targets in microtubule assembly. Science. 2001 Jan 26;291(5504):653–656. doi: 10.1126/science.1057661. [DOI] [PubMed] [Google Scholar]
- Wilcox M., DiAntonio A., Leptin M. The function of PS integrins in Drosophila wing morphogenesis. Development. 1989 Dec;107(4):891–897. doi: 10.1242/dev.107.4.891. [DOI] [PubMed] [Google Scholar]
- Wilcox M. Genetic analysis of the Drosophila PS integrins. Cell Differ Dev. 1990 Dec 2;32(3):391–399. doi: 10.1016/0922-3371(90)90055-2. [DOI] [PubMed] [Google Scholar]
- Xu T., Rubin G. M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development. 1993 Apr;117(4):1223–1237. doi: 10.1242/dev.117.4.1223. [DOI] [PubMed] [Google Scholar]
- Yamada K. M., Miyamoto S. Integrin transmembrane signaling and cytoskeletal control. Curr Opin Cell Biol. 1995 Oct;7(5):681–689. doi: 10.1016/0955-0674(95)80110-3. [DOI] [PubMed] [Google Scholar]
- Yu D. H., Qu C. K., Henegariu O., Lu X., Feng G. S. Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. J Biol Chem. 1998 Aug 14;273(33):21125–21131. doi: 10.1074/jbc.273.33.21125. [DOI] [PubMed] [Google Scholar]
- Zavortink M., Bunch T. A., Brower D. L. Functional properties of alternatively spliced forms of the Drosophila PS2 integrin alpha subunit. Cell Adhes Commun. 1993 Dec;1(3):251–264. doi: 10.3109/15419069309097258. [DOI] [PubMed] [Google Scholar]