A Transmembrane Leucine Zipper Is Required for Activation of the Dimeric Receptor Tyrosine Kinase DDR1

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Abstract

Receptor tyrosine kinases of the discoidin domain family, DDR1 and DDR2, are activated by different types of collagen and play important roles in cell adhesion, migration, proliferation, and matrix remodeling. In a previous study, we found that collagen binding by the discoidin domain receptors (DDRs) requires dimerization of their extracellular domains (Leitinger, B. (2003) J. Biol. Chem. 278, 16761-16769), indicating that the paradigm of ligand-induced receptor dimerization may not apply to the DDRs. Using chemical cross-linking and co-immunoprecipitation of differently tagged DDRs, we now show that the DDRs form ligand-independent dimers in the biosynthetic pathway and on the cell surface. We further show that both the extracellular and the cytoplasmic domains are individually dispensable for DDR1 dimerization. The DDR1 transmembrane domain contains two putative dimerization motifs, a leucine zipper and a GXXXG motif. Mutations disrupting the leucine zipper strongly impaired collagen-induced transmembrane signaling, although the mutant DDR1 proteins were still able to dimerize, whereas mutation of the GXXXG motif had no effect. A bacterial reporter assay (named TOXCAT) showed that the DDR1 transmembrane domain has a strong potential for self-association in a biological membrane and that this interaction occurs via the leucine zipper and not the GXXXG motif. Our results demonstrate that the DDRs exist as stable dimers in the absence of ligand and that receptor activation requires specific interactions made by the transmembrane leucine zipper. Receptor tyrosine kinases of the discoidin domain family, DDR1 and DDR2, are activated by different types of collagen and play important roles in cell adhesion, migration, proliferation, and matrix remodeling. In a previous study, we found that collagen binding by the discoidin domain receptors (DDRs) requires dimerization of their extracellular domains (Leitinger, B. (2003) J. Biol. Chem. 278, 16761-16769), indicating that the paradigm of ligand-induced receptor dimerization may not apply to the DDRs. Using chemical cross-linking and co-immunoprecipitation of differently tagged DDRs, we now show that the DDRs form ligand-independent dimers in the biosynthetic pathway and on the cell surface. We further show that both the extracellular and the cytoplasmic domains are individually dispensable for DDR1 dimerization. The DDR1 transmembrane domain contains two putative dimerization motifs, a leucine zipper and a GXXXG motif. Mutations disrupting the leucine zipper strongly impaired collagen-induced transmembrane signaling, although the mutant DDR1 proteins were still able to dimerize, whereas mutation of the GXXXG motif had no effect. A bacterial reporter assay (named TOXCAT) showed that the DDR1 transmembrane domain has a strong potential for self-association in a biological membrane and that this interaction occurs via the leucine zipper and not the GXXXG motif. Our results demonstrate that the DDRs exist as stable dimers in the absence of ligand and that receptor activation requires specific interactions made by the transmembrane leucine zipper. Receptor tyrosine kinases (RTKs) 5The abbreviations used are: RTK, receptor tyrosine kinase; ECD, extracellular domain; DDR, discoidin domain receptor; DS, discoidin homology; TM, transmembrane; HEK, human embryonic kidney; BS3, bis(sulfonsuccinimidyl) suberate; GpA, glycophorin A; MBP, maltose-binding protein; PBS, phosphate-buffered saline; CAT, chloramphenicol acetyltransferase; ELISA, enzyme-linked immunosorbent assay; Ab, antibody; mAb, monoclonal antibody.5The abbreviations used are: RTK, receptor tyrosine kinase; ECD, extracellular domain; DDR, discoidin domain receptor; DS, discoidin homology; TM, transmembrane; HEK, human embryonic kidney; BS3, bis(sulfonsuccinimidyl) suberate; GpA, glycophorin A; MBP, maltose-binding protein; PBS, phosphate-buffered saline; CAT, chloramphenicol acetyltransferase; ELISA, enzyme-linked immunosorbent assay; Ab, antibody; mAb, monoclonal antibody. control many fundamental cellular processes, such as cell proliferation, differentiation, migration, and metabolism. RTK activity normally is under tight control, and dysregulated RTK activation is associated with most cancers, making RTKs important targets for cancer therapy (1Krause D.S. Van Etten R.A. N. Engl. J. Med. 2005; 353: 172-187Crossref PubMed Scopus (1158) Google Scholar). RTKs allow the cell to respond to external cues; ligand binding to the extracellular domain (ECD) of RTKs results in transphosphorylation of their cytoplasmic domains, which in turn leads to downstream signaling. The prevailing model of RTK activation states that receptors are monomeric in the absence of ligand but become dimerized upon ligand binding; dimerization brings the cytoplasmic domains in close proximity, favoring transphosphorylation (2Schlessinger J. Cell. 2000; 103: 211-225Abstract Full Text Full Text PDF PubMed Scopus (3502) Google Scholar). However, some studies have found dimerized RTKs in the absence of ligand, suggesting that activation may involve ligand-induced conformational changes within a dimeric receptor (e.g. Refs. 3Moriki T. Maruyama H. Maruyama I.N. J. Mol. Biol. 2001; 311: 1011-1026Crossref PubMed Scopus (276) Google Scholar, 4Yu X. Sharma K.D. Takahashi T. Iwamoto R. Mekada E. Mol. Biol. Cell. 2002; 13: 2547-2557Crossref PubMed Scopus (177) Google Scholar, 5Martin-Fernandez M. Clarke D.T. Tobin M.J. Jones S.V. Jones G.R. Biophys. J. 2002; 82: 2415-2427Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). The discoidin domain receptor (DDR) family of RTKs consists of two members, DDR1 and DDR2, that are characterized by the presence of an extracellular discoidin homology (DS) domain. Uniquely among RTKs, the DDRs are activated by a major extracellular matrix component, triple-helical collagen (6Shrivastava A. Radziejewski C. Campbell E. Kovac L. McGlynn M. Ryan T.E. Davis S. Goldfarb M.P. Glass D.J. Lemke G. Yancopoulos G.D. Mol. Cell. 1997; 1: 25-34Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 7Vogel W. Gish G.D. Alves F. Pawson T. Mol. Cell. 1997; 1: 13-23Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar). Several collagen types bind to and activate the DDRs, with the two receptors displaying different specificities toward certain collagen types (6Shrivastava A. Radziejewski C. Campbell E. Kovac L. McGlynn M. Ryan T.E. Davis S. Goldfarb M.P. Glass D.J. Lemke G. Yancopoulos G.D. Mol. Cell. 1997; 1: 25-34Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 7Vogel W. Gish G.D. Alves F. Pawson T. Mol. Cell. 1997; 1: 13-23Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar, 8Leitinger B. Steplewski A. Fertala A. J. Mol. Biol. 2004; 344: 993-1003Crossref PubMed Scopus (78) Google Scholar). The DDRs are widely expressed in normal and malignant tissues and control developmental processes; DDR1 is essential for mammary gland development in the mouse (9Vogel W.F. Aszodi A. Alves F. Pawson T. Mol. Cell. Biol. 2001; 21: 2906-2917Crossref PubMed Scopus (250) Google Scholar), and DDR2 controls bone growth through chondrocyte proliferation (10Labrador J.P. Azcoitia V. Tuckermann J. Lin C. Olaso E. Manes S. Bruckner K. Goergen J.L. Lemke G. Yancopoulos G. Angel P. Martinez A.C. Klein R. EMBO Rep. 2001; 2: 446-452Crossref PubMed Scopus (217) Google Scholar). Both receptors regulate cell proliferation, adhesion, and motility and control remodeling of the extracellular matrix by regulating the expression and activity of matrix metalloproteinases (11Hou G. Vogel W. Bendeck M.P. J. Clin. Investig. 2001; 107: 727-735Crossref PubMed Scopus (185) Google Scholar, 12Olaso E. Ikeda K. Eng F.J. Xu L. Wang L.H. Lin H.C. Friedman S.L. J. Clin. Investig. 2001; 108: 1369-1378Crossref PubMed Scopus (245) Google Scholar, 13Olaso E. Labrador J.P. Wang L. Ikeda K. Eng F.J. Klein R. Lovett D.H. Lin H.C. Friedman S.L. J. Biol. Chem. 2002; 277: 3606-3613Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 14Ferri N. Carragher N.O. Raines E.W. Am. J. Pathol. 2004; 164: 1575-1585Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). With respect to human disease, the DDRs are associated with cancer (15Dejmek J. Leandersson K. Manjer J. Bjartell A. Emdin S.O. Vogel W.F. Landberg G. Andersson T. Clin. Cancer Res. 2005; 11: 520-528PubMed Google Scholar, 16Heinzelmann-Schwarz V.A. Gardiner-Garden M. Henshall S.M. Scurry J. Scolyer R.A. Davies M.J. Heinzelmann M. Kalish L.H. Bali A. Kench J.G. Edwards L.S. Vanden Bergh P.M. Hacker N.F. Sutherland R.L. O'Brien P.M. Clin. Cancer Res. 2004; 10: 4427-4436Crossref PubMed Scopus (177) Google Scholar, 17Ongusaha P.P. Kim J.I. Fang L. Wong T.W. Yancopoulos G.D. Aaronson S.A. Lee S.W. EMBO J. 2003; 22: 1289-1301Crossref PubMed Scopus (146) Google Scholar, 18Evtimova V. Zeillinger R. Weidle U.H. Tumour Biol. 2003; 24: 189-198Crossref PubMed Scopus (34) Google Scholar, 19Wall S.J. Werner E. Werb Z. DeClerck Y.A. J. Biol. Chem. 2005; 280: 40187-40194Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 20Ram R. Lorente G. Nikolich K. Urfer R. Foehr E. Nagavarapu U. J. Neurooncol. 2006; 76: 239-248Crossref PubMed Scopus (93) Google Scholar), fibrotic diseases of the lung and liver (12Olaso E. Ikeda K. Eng F.J. Xu L. Wang L.H. Lin H.C. Friedman S.L. J. Clin. Investig. 2001; 108: 1369-1378Crossref PubMed Scopus (245) Google Scholar, 21Matsuyama W. Watanabe M. Shirahama Y. Oonakahara K. Higashimoto I. Yoshimura T. Osame M. Arimura K. J. Immunol. 2005; 174: 6490-6498Crossref PubMed Scopus (34) Google Scholar), atherosclerosis (14Ferri N. Carragher N.O. Raines E.W. Am. J. Pathol. 2004; 164: 1575-1585Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), and osteoarthritis (22Xu L. Peng H. Wu D. Hu K. Goldring M.B. Olsen B.R. Li Y. J. Biol. Chem. 2005; 280: 548-555Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). DDR1 and DDR2 share the same domain architecture: an ECD consisting of an N-terminal DS domain followed by a unique sequence of ∼200 amino acids; a single-span transmembrane (TM) domain; an unusually large cytosolic juxtamembrane domain; and a C-terminal tyrosine kinase domain. In a previous study, we found that DDR activation, manifested by receptor autophosphorylation, is a consequence of collagen binding to a specific site within the DDR DS domain (23Leitinger B. J. Biol. Chem. 2003; 278: 16761-16769Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). We also observed that collagen binding by the DDRs requires dimerization of their ECDs (23Leitinger B. J. Biol. Chem. 2003; 278: 16761-16769Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar), but how this observation relates to the oligomeric state of full-length DDRs within the cell membrane and the activation mechanism remained unclear. In the present study, we have analyzed the oligomerization state of full-length DDRs in their natural environment, the mammalian cell membrane. We show that the DDRs form ligand-independent dimers, both in the endoplasmic reticulum and at the cell surface. Neither the ECD nor the cytoplasmic domain of DDR1 is required for this interaction. In contrast, a leucine zipper motif in the DDR1 TM domain mediates strong self-association in a bacterial cell membrane and is essential for DDR1 activation in mammalian cells. Our findings demonstrate that the activation mechanism of DDRs is unlikely to involve ligand-induced receptor dimerization. Cell Culture—Human embryonic kidney (HEK) 293 cells were as (23Leitinger B. J. Biol. Chem. 2003; 278: 16761-16769Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). and collagen and were A and were The and their were as and mouse The the ECD, a were as and were were with The were by for expression in cells were the mammalian expression used for the mutant on The of the DDR1 and (23Leitinger B. J. Biol. Chem. 2003; 278: 16761-16769Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). The same used for the of the The cytoplasmic DDR1 a The cytoplasmic made by full-length a The same were used to the two and but the and The TM were by that the The were made as The expression and and the U. S. A. PubMed Scopus Google were a of The for the proteins with DDR1 TM domains were by of which were a The were by and cells. of for at the of in a of of were to cells in The by the of and at for followed by cell cells at were by as (23Leitinger B. J. Biol. Chem. 2003; 278: 16761-16769Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). were with and with of the were also as cells were on in The by at and were to with mouse were with A to The were with The proteins were analyzed by on followed by The were with mouse followed by to by Cell of cells DDR1 as The cells were with in for on The by with in The cells were in and of cell for with to bind cell The were by and the for with to cell The the and were and in and in to The the and with to the DDR receptor the DDR in the of of with for DDR a control for an were by and analyzed by with DDR assay as (23Leitinger B. J. Biol. Chem. 2003; 278: 16761-16769Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). cells in were by with the DDR expression the cells were with for were with collagen for at were in of the were analyzed by followed by The were with mouse followed by by the were in at for for at The were with followed by for the ELISA, of cells were of as a unique of and The bacterial were at with to of and by of at for at The cell were with at and in of The cells were for at and of the were for a to the of of cells were in with to of were of bacterial and in were by the of and for The were by and with as followed by to by DDR the DDRs exist as in the absence of we chemical cross-linking cells were with human DDR1 DDR2 and in the presence absence of the The DDRs were by of cell In the absence of DDR1 is observed to as two of and The the biosynthetic of the whereas the DDR1 not and M. X. Vogel W.F. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In the presence of BS3, an to the of a DDR1 by the for DDR2, which as a of with the two not a in the presence of BS3, which to the of dimeric results that the DDRs, at a of exist as dimers on the cell in the absence of the of DDR we co-immunoprecipitation two differently DDR Both DDR1 and DDR2 were tagged at the with a a receptor were expressed with the same as their the same of and showed the receptors not expression in and DDR1 with and not The specific and not and not co-immunoprecipitation and were cells. Cell were with Ab, and the analyzed by with that with the Ab, indicating that and with in cells with both types of tagged DDR1 but not of cells were that requires the tagged receptors to expressed on the same cell membrane and receptor cell is that both the and the of with expressed in the same cell results were with DDR2 We results the and of cells the two of the DDRs with the followed by with the not we that DDR1 and DDR2 to form and that dimerization the of DDRs on the cell surface. We also collagen binding the of DDR dimers on the cell surface. both types of tagged DDRs were to co-immunoprecipitation in the presence absence of collagen both DDR1 and DDR2, no in the of DDR co-immunoprecipitation and not indicating that collagen binding not DDR dimerization on the cell surface. Neither the nor the of DDR1 for DDR1 to which domains in DDR1 are for We made a of and to dimerization by both cross-linking and The extracellular domain of DDR1 is of an N-terminal DS domain followed by a domain unique to DDRs. The of the DDR1 ECD are in and The cytoplasmic domain is of an unusually juxtamembrane domain amino in followed by the tyrosine kinase domain. the cytoplasmic domain nor of the DDR1 ECD were found to essential for dimerization as of the in the co-immunoprecipitation assay and not The cytoplasmic were by BS3, with to the of the proteins and the for for The of to the of proteins strong that the cross-linking assay DDR with of the extracellular and not We used cell to which of the were to the cell surface. a the of the DDR1 proteins to by and their A and that the cross-linking assay that DDR1 dimerization is to interactions the ECD which domain within a we two different ECD that are not to able to via their The the DDR1 DS domain but in an close to the TM domain. The on the is the DS domain and the of the DDR1 studies no in the of proteins to that the DDR1 ECD is dispensable for DDR1 dimerization. A the DS domain in the ECD with the cytoplasmic domain also showed interaction in the co-immunoprecipitation assay indicating in the absence of the cytoplasmic the DS domain and the TM domain are for DDR1 dimerization. The of the DDR1 TM in and the DDR1 TM domain is to of the in dimerization that the TM domain to interactions the DDR1 The DDR1 TM domain contains two putative dimerization is a GXXXG motif in the M.J. PubMed Scopus Google Scholar, J. Mol. Biol. 2000; PubMed Scopus Google Scholar), which is the of the dimerization of the strongly TM domain of glycophorin A 1997; PubMed Scopus Google Scholar). GXXXG are also important for TM interactions of receptors M.B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). In to the GXXXG the DDR1 TM sequence also contains of which are to TM domain dimerization in a as in leucine R. R. B. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). A dimeric leucine zipper is a of two through in a and of a 2004; PubMed Scopus Google Scholar). which of the potential dimerization are important for DDR1 dimerization TM signaling, we DDR1 TM via the leucine we and to previous on R. D. J. Cell PubMed Google and the receptor W. R. J. R. D. D. U. Biol. 2001; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). The GXXXG motif the amino in the of the M.J. PubMed Scopus Google Scholar). via the GXXXG in the to the to to previous on receptors M.B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). the mutation is with of a leucine zipper. The mutant were made in the of full-length DDR1 and We the mutant for their to of the showed dimerization to the same as as both by cross-linking of cell receptors with and by co-immunoprecipitation of and receptors the GXXXG motif nor the leucine zipper motif is essential for dimerization of full-length co-immunoprecipitation of an that to DDR1 the ECD W.F. 2002; PubMed Scopus Google Scholar). also observed with DDR1 not and presence in the further that the ECD is not required for DDR1 dimerization. activation of DDR1 followed by receptor (6Shrivastava A. Radziejewski C. Campbell E. Kovac L. McGlynn M. Ryan T.E. Davis S. Goldfarb M.P. Glass D.J. Lemke G. Yancopoulos G.D. Mol. Cell. 1997; 1: 25-34Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 7Vogel W. Gish G.D. Alves F. Pawson T. Mol. Cell. 1997; 1: 13-23Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar). The of the TM on collagen-induced DDR1 analyzed in which were with different of collagen I. The leucine zipper and strongly impaired receptor activation at collagen In contrast, the GXXXG showed autophosphorylation, to DDR1 results demonstrate that the leucine zipper motif in the DDR1 TM but not the GXXXG is essential for DDR1 signaling, suggesting that TM signaling, the DDR1 TM domains are associated via a leucine zipper. The DDR1 in the DDR1 TM domain via a leucine zipper in a biological we used the by and U. S. A. PubMed Scopus Google Scholar). In this a consisting of an N-terminal the TM domain of and a C-terminal domain is expressed in the membrane of E. via the TM sequence cytoplasmic in activation of a reporter activity is and to to the of TM dimerization. In the the of the TM sequence and the of the the TM and the and are important for the of expression as the of the TM in the membrane the of the domains with respect to the TM We the of different DDR1 TM the by amino the of the DDR1 TM domain DDR1 proteins showed strong of activity activity that of a control a a strong self-association of the DDR1 TM domain. activity is also to the of we the expression of proteins by of bacterial proteins were expressed at is that although the showed some as observed in the U. S. A. PubMed Scopus Google no were observed for the DDR1 the DDR1 to stable the the strong of activity of the with the the of the DDR1 in the we the same the the activity in the that the two leucine zipper and strongly whereas the GXXXG had the same activity as The of the and is most in the activity assay as we observed the and mutant to expressed at the and results demonstrate that the DDR1 TM in a bacterial cell membrane via a leucine zipper. A widely mechanism of RTK activation receptor dimerization (2Schlessinger J. Cell. 2000; 103: 211-225Abstract Full Text Full Text PDF PubMed Scopus (3502) Google Scholar). we present that the DDRs, an family of RTKs activated by may respond to ligand binding by a conformational within a that results in of the cytosolic We that DDR dimerization occurs biosynthetic to the cell surface. We that DDR dimers are the on the cell with previous that dimerization of the DDR ECD is a for collagen binding (23Leitinger B. J. Biol. Chem. 2003; 278: 16761-16769Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). RTK dimerization is not Several studies have growth receptor dimers, suggesting that activation may conformational within a T. Maruyama H. Maruyama I.N. J. Mol. Biol. 2001; 311: 1011-1026Crossref PubMed Scopus (276) Google Scholar, 4Yu X. Sharma K.D. Takahashi T. Iwamoto R. Mekada E. Mol. Biol. Cell. 2002; 13: 2547-2557Crossref PubMed Scopus (177) Google Scholar, 5Martin-Fernandez M. Clarke D.T. Tobin M.J. Jones S.V. Jones G.R. Biophys. J. 2002; 82: 2415-2427Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, T.W. J. Cell Biol. PubMed Scopus Google Scholar). receptor is a that is activated by ligand further oligomerization 2000; PubMed Scopus Google Scholar). In which are to share many with RTKs, the ligand-induced dimerization model has by the findings that both the and the growth receptors ligand-independent dimerization T. M. H. U. S. A. 2001; PubMed Scopus Google Scholar, J. P. M. G. U. S. A. 2002; PubMed Scopus Google Scholar, R.A. Y. K. M.J. Mol. Biol. 2005; PubMed Scopus Google Scholar). DDR1 are essential for we found that the ECD nor the cytoplasmic domain is required for we on the TM which contains two potential dimerization motifs, a GXXXG and a leucine zipper motif. The GXXXG motif is found in the TM domains of RTKs M.J. PubMed Scopus Google and has to TM dimerization of receptors M.B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, D. N. Y. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). have found to important for oligomeric of a of single-span TM the receptor W. R. J. R. D. D. U. Biol. 2001; 11: Full Text Full Text PDF PubMed Scopus Google Scholar, W. V. U. D. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google and R. D. J. Cell PubMed Google Scholar). we found that of motif in full-length DDR1 The results that no domain in DDR1 is for dimerization but that interactions the DDR1 TM, and cytosolic in is to the DDR1 TM domain in mammalian we used the bacterial reporter assay to a of TM dimerization U. S. A. PubMed Scopus Google Scholar). The DDR1 TM domain showed a strong for which impaired by mutation of the leucine zipper motif but not of the GXXXG motif. the DDR1 TM domain in a biological membrane via the leucine zipper motif. mutation of the TM leucine zipper to dimerization of full-length had a on DDR1 of the leucine zipper but not of the GXXXG collagen-induced of DDR1 to suggesting that specific interactions made by the leucine zipper are in the conformational ligand to the cytosolic kinase we not the of this conformational a mechanism involve the of receptor within the as for the growth receptor T. Maruyama H. Maruyama I.N. J. Mol. Biol. 2001; 311: 1011-1026Crossref PubMed Scopus (276) Google Scholar), the receptor N. Y. J. V. S. S.O. Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus (162) Google Scholar), and the growth receptor R.A. Y. K. M.J. Mol. Biol. 2005; PubMed Scopus Google Scholar). of the DDRs still a is their unusually and activation (6Shrivastava A. Radziejewski C. Campbell E. Kovac L. McGlynn M. Ryan T.E. Davis S. Goldfarb M.P. Glass D.J. Lemke G. Yancopoulos G.D. Mol. Cell. 1997; 1: 25-34Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 7Vogel W. Gish G.D. Alves F. Pawson T. Mol. Cell. 1997; 1: 13-23Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar). unlikely that conformational changes within a DDR on a of and processes, such as receptor may in DDR In findings show that the DDRs exist as stable dimers in the absence of ligand and that receptor activation requires specific interactions made by the transmembrane leucine zipper. We and for the and for and with the with

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Venue

Journal of Biological Chemistry

Topic

Cell Adhesion Molecules Research

Field

Medicine

Canadian institutions

not available

Funders

Wellcome Trust

Keywords

Leucine zipperReceptor tyrosine kinaseChemistryZipperTransmembrane proteinBasic helix-loop-helix leucine zipper transcription factorsTyrosine kinaseTropomyosin receptor kinase CProto-oncogene tyrosine-protein kinase SrcROR1bZIP domainBiochemistryCell biologyKinaseReceptorBiologyPlatelet-derived growth factor receptorTranscription factorComputer scienceGeneDNA-binding protein

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