Rab Coupling Protein (RCP), a Novel Rab4 and Rab11 Effector Protein

Abstract

Rab4 and Rab11 are small GTPases belonging to the Ras superfamily. They both function as regulators along the receptor recycling pathway. We have identified a novel 80-kDa protein that interacts specifically with the GTP-bound conformation of Rab4, and subsequent work has shown that it also interacts strongly with Rab11. We name this protein Rab coupling protein (RCP). RCP is predominantly membrane-bound and is expressed in all cell lines and tissues tested. It colocalizes with early endosomal markers including Rab4 and Rab11 as well as with the transferrin receptor. Overexpression of the carboxyl-terminal region of RCP, which contains the Rab4- and Rab11-interacting domain, results in a dramatic tubulation of the transferrin compartment. Furthermore, expression of this mutant causes a significant reduction in endosomal recycling without affecting ligand uptake or degradation in quantitative assays. RCP is a homologue of Rip11 and therefore belongs to the recently described Rab11-FIP family. Rab4 and Rab11 are small GTPases belonging to the Ras superfamily. They both function as regulators along the receptor recycling pathway. We have identified a novel 80-kDa protein that interacts specifically with the GTP-bound conformation of Rab4, and subsequent work has shown that it also interacts strongly with Rab11. We name this protein Rab coupling protein (RCP). RCP is predominantly membrane-bound and is expressed in all cell lines and tissues tested. It colocalizes with early endosomal markers including Rab4 and Rab11 as well as with the transferrin receptor. Overexpression of the carboxyl-terminal region of RCP, which contains the Rab4- and Rab11-interacting domain, results in a dramatic tubulation of the transferrin compartment. Furthermore, expression of this mutant causes a significant reduction in endosomal recycling without affecting ligand uptake or degradation in quantitative assays. RCP is a homologue of Rip11 and therefore belongs to the recently described Rab11-FIP family. The large number of Rab proteins identified in mammalian cell lines and their localization to specific compartments within the cell suggest that they each play a crucial and specific role in the transport process. Rabs cycle between a membrane-bound state and a cytosolic state. This cycling is guanine nucleotide-dependent and is regulated by various accessory factors. Several Rab proteins including Rab4, -5, -7, -9, and -11 are known to be involved in the process of endocytosis (1.Somsel Rodman J. Wandinger-Ness A. J. Cell Sci. 2000; 113: 183-192Crossref PubMed Google Scholar). Rab5 is important in the homotypic fusion between early endosomes as well as in the transport to the early endosomal compartment (2.Gorvel J.P. Chavrier P. Zerial M. Gruenberg J. Cell. 1991; 64: 915-925Abstract Full Text PDF PubMed Scopus (890) Google Scholar, 3.Stenmark H. Parton R.G. Steele-Mortimer O. Lutcke A. Gruenberg J. Zerial M. EMBO J. 1994; 13: 1287-1296Crossref PubMed Scopus (784) Google Scholar). Additionally, it seems to be necessary for the budding of vesicles from the plasma membrane (4.McLauchlan H. Newell J. Morrice N. Osborne A. West M. Smythe E. Curr. Biol. 1998; 8: 34-45Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). Rab4 has been localized to the early endosomal compartment and affects recycling (5.van der Sluijs P. Hull M. Webster P. Male P. Goud B. Mellman I. Cell. 1992; 70: 729-740Abstract Full Text PDF PubMed Scopus (520) Google Scholar, 6.van der Sluijs P. Hull M. Zahraoui A. Tavitian A. Goud B. Mellman I. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6313-6317Crossref PubMed Scopus (233) Google Scholar) as well as trafficking to the late endosomal compartment (7.McCaffrey M. Bielli A. Cantalupo G. Mora S. Roberti V. Santillo M. Drummond F. Bucci C. FEBS Lett. 2001; 495: 21-30Crossref PubMed Scopus (141) Google Scholar). Considering the localization and functional effects of Rab4, it is likely that it controls traffic through/from the early sorting endosomes. Rab11 has been localized to the recycling compartment (8.Ullrich O. Reinsch S. Urbe S. Zerial M. Parton R.G. J. Cell Biol. 1996; 135: 913-924Crossref PubMed Scopus (1098) Google Scholar) and to trans-Golgi network (TGN) 1The abbreviations used are: TGNtrans-Golgi networkERCendosomal recycling compartmentRCPRab coupling proteinBHK cellsbaby hamster kidney cellsWTwild typeCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidFITCfluorescein isothiocyanateTfntransferrinTfnRTfn receptorEEA1endosome-associated antigen 1 membranes (9.Urbe S. Huber L.A. Zerial M. Tooze S.A. Parton R.G. FEBS Lett. 1993; 334: 175-182Crossref PubMed Scopus (190) Google Scholar) and controls endosomal recycling (8.Ullrich O. Reinsch S. Urbe S. Zerial M. Parton R.G. J. Cell Biol. 1996; 135: 913-924Crossref PubMed Scopus (1098) Google Scholar) as well as traffic to the Golgi apparatus (10.Wilcke M. Johannes L. Galli T. Mayau V. Goud B. Salamero J. J. Cell Biol. 2000; 151: 1207-1220Crossref PubMed Scopus (322) Google Scholar). Rab4 and Rab11 have been shown by multicolor imaging (11.Sonnichsen B. De Renzis S. Nielsen E. Rietdorf J. Zerial M. J. Cell Biol. 2000; 149: 901-914Crossref PubMed Scopus (820) Google Scholar) and by biochemical experimentation (12.Trischler M. Stoorvogel W. Ullrich O. J. Cell Sci. 1999; 112: 4773-4783Crossref PubMed Google Scholar) to overlap in their localization along the endocytic pathway. Rab7 and -9 are localized to the late endosomal compartment (13.Chavrier P. Parton R.G. Hauri H.P. Simons K. Zerial M. Cell. 1990; 62: 317-329Abstract Full Text PDF PubMed Scopus (935) Google Scholar, 14.Lombardi D. Soldati T. Riederer M.A. Goda Y. Zerial M. Pfeffer S.R. EMBO J. 1993; 12: 677-682Crossref PubMed Scopus (445) Google Scholar) and control late endocytic trafficking (15.Meresse S. Gorvel J.P. Chavrier P. J. Cell Sci. 1995; 108: 3349-3358PubMed Google Scholar, 16.Feng Y. Press B. Wandinger-Ness A. J. Cell Biol. 1995; 131: 1435-1452Crossref PubMed Scopus (541) Google Scholar, 17.Vitelli R. Santillo M. Lattero D. Chiariello M. Bifulco M. Bruni C.B. Bucci C. J. Biol. Chem. 1997; 272: 4391-4397Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 18.Bucci C. Thomsen P. Nicoziani P. McCarthy J. van Deurs B. Mol. Biol. Cell. 2000; 11: 467-480Crossref PubMed Scopus (822) Google Scholar) and trafficking from late endosomes to the trans-Golgi Network (14.Lombardi D. Soldati T. Riederer M.A. Goda Y. Zerial M. Pfeffer S.R. EMBO J. 1993; 12: 677-682Crossref PubMed Scopus (445) Google Scholar), respectively. trans-Golgi network endosomal recycling compartment Rab coupling protein baby hamster kidney cells wild type 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid fluorescein isothiocyanate transferrin Tfn receptor endosome-associated antigen 1 An essential task in elucidating the function of Rab proteins is to identify their interacting proteins. Several such proteins have already been identified, including rabaptin 5, a 100-kDA protein with two pairs of coiled-coil regions, which was initially found in a yeast two-hybrid screen to identify effectors of Rab5 (19.Stenmark H. Vitale G. Ullrich O. Zerial M. Cell. 1995; 83: 423-432Abstract Full Text PDF PubMed Scopus (403) Google Scholar) and has subsequently been shown to also interact with Rab4 (20.Vitale G. Rybin V. Christoforidis S. Thornqvist P. McCaffrey M. Stenmark H. Zerial M. EMBO J. 1998; 17: 1941-1951Crossref PubMed Scopus (197) Google Scholar). Several other Rab4-interacting proteins have also been identified, including rabaptin 4 (21.Nagelkerken B. Van Anken E. Van Raak M. Gerez L. Mohrmann K. Van Uden N. Holthuizen J. Pelkmans L. Van Der Sluijs P. Biochem. J. 2000; 3: 593-601Crossref Google Scholar), syntaxin 4 (22.Li L. Omata W. Kojima I. Shibata H. J. Biol. Chem. 2001; 276: 5265-5273Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar), Rab4-interacting protein (Rab4ip) (23.Cormont M. Mari M. Galmiche A. Hofman P. Le Marchand-Brustel Y. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1637-1642Crossref PubMed Scopus (88) Google Scholar), and the dynein light intermediate 1 A. R. K. McCaffrey Biochem. 2001; PubMed Scopus Google Scholar). A. T. I. T. Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google J. M. D. De C. M. H. P. G. T. M. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar), R. J. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), L.A. R. J. M. Mol. Biol. Cell. 2001; 12: PubMed Scopus Google Scholar), and the Rab11-FIP have been identified as interacting of Rab11 R. D. R. J. L.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the function of Rab4, a yeast two-hybrid screen was to identify proteins that interact with the GTP-bound of the of a protein that interacts with Rab4 and Rab11. We the protein to the early endosomal recycling compartment and that of a mutant of this protein the of this compartment and strongly endosomal of with two Rabs that function in endosomal localization to the early endosomal recycling and functional effects the recycling to name this the Rab coupling protein (RCP). this protein is to the Rab11-interacting protein R. J. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) belongs to the recently Rab11-FIP protein R. D. R. J. L.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The Rab4 two-hybrid have been described A. R. K. McCaffrey Biochem. 2001; PubMed Scopus Google Scholar). and from M. Zerial (19.Stenmark H. Vitale G. Ullrich O. Zerial M. Cell. 1995; 83: 423-432Abstract Full Text PDF PubMed Scopus (403) Google Scholar), and and from A. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). have been described I. F. J. Goud B. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), and by the Rab11 and as from the described (10.Wilcke M. Johannes L. Galli T. Mayau V. Goud B. Salamero J. J. Cell Biol. 2000; 151: 1207-1220Crossref PubMed Scopus (322) Google Scholar). was by as was used as the in the with and the The from this was used as the in a with the The was and by the from the of and respectively. was by the from the of was from a the and The was with and and RCP was from The that the RCP was the by the F. S. 1992; Google Scholar). The yeast two-hybrid screen was as described S. PubMed Scopus Google Scholar). the yeast Cell. 1993; Full Text PDF PubMed Scopus Google Scholar) was with and This was with Cell. 1993; Full Text PDF PubMed Scopus Google Scholar) in The for in and and and and for cells was as 1 of from each of a was used as in a with the RCP and The to the region of RCP to a of An of and of 1 was used as in the control and the control 1 of of The and protein as E. cells with or to and with for The proteins with to a was for used receptor and was used to and expressed as fusion proteins in the acid was a from J. The Rab11 has been described (10.Wilcke M. Johannes L. Galli T. Mayau V. Goud B. Salamero J. J. Cell Biol. 2000; 151: 1207-1220Crossref PubMed Scopus (322) Google Scholar). was as from a was as described B. Zahraoui A. Tavitian A. J. 1990; PubMed Scopus Google Scholar). The was a of for and for of the was to and in of the Rab protein was in 4 with of for 1 the the was to and the Rab protein was to of 1 which was with the for 1 The for with and a and cells in as described A. R. K. McCaffrey Biochem. 2001; PubMed Scopus Google Scholar). cells in essential with and cells for with the from G. or the and with the or to the with was cells the to the of the the cells and for with with with and with the in The used to fluorescein isothiocyanate and to or to The with a as described A. F. O. A. I. Goud B. 1998; PubMed Scopus Google Scholar) or by a with a and cells to for 1 The cells with and as the was for and for The cells with and cells in by and a and for and by the for 1 4 in a as described H. E. R. D. EMBO J. 2000; PubMed Scopus Google the was with 1 or for and for 1 4 The membranes in the as and of by and The recycling as described (8.Ullrich O. Reinsch S. Urbe S. Zerial M. Parton R.G. J. Cell Biol. 1996; 135: 913-924Crossref PubMed Scopus (1098) Google Scholar). cells with the with the and the was to the cell for 1 ligand was and the cells to and the the of Tfn in the was the of recycling from the recycling the cells with for ligand was and the cells for the the of in the was all the is as a of the Tfn with the cell Tfn in the cells with the We the yeast two-hybrid to identify proteins that interact with therefore mutant of Rab4 was used as to screen of which and the of a nucleotide-dependent with and of the to be rabaptin 5, a Rab5 that also interacts with Rab4 (20.Vitale G. Rybin V. Christoforidis S. Thornqvist P. McCaffrey M. Stenmark H. Zerial M. EMBO J. 1998; 17: 1941-1951Crossref PubMed Scopus (197) Google Scholar). by expressed The from the screen have to be was for this and that it interacts strongly with and with the mutant was with a mutant that is has acid in the that the is this was with the of or Rab7 was also a with all Rab11 results that a that interacts with two early endosomal Rab GTPases that have been shown to overlap in their localization (11.Sonnichsen B. De Renzis S. Nielsen E. Rietdorf J. Zerial M. J. Cell Biol. 2000; 149: 901-914Crossref PubMed Scopus (820) Google Scholar, M. Stoorvogel W. Ullrich O. J. Cell Sci. 1999; 112: 4773-4783Crossref PubMed Google Scholar) and function (5.van der Sluijs P. Hull M. Webster P. Male P. Goud B. Mellman I. Cell. 1992; 70: 729-740Abstract Full Text PDF PubMed Scopus (520) Google Scholar, 6.van der Sluijs P. Hull M. Zahraoui A. Tavitian A. Goud B. Mellman I. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6313-6317Crossref PubMed Scopus (233) Google Scholar, M. Bielli A. Cantalupo G. Mora S. Roberti V. Santillo M. Drummond F. Bucci C. FEBS Lett. 2001; 495: 21-30Crossref PubMed Scopus (141) Google Scholar, O. Reinsch S. Urbe S. Zerial M. Parton R.G. J. Cell Biol. 1996; 135: 913-924Crossref PubMed Scopus (1098) Google Scholar) in the of receptor Furthermore, in a Rab4 two-hybrid screen A. R. K. McCaffrey Biochem. 2001; PubMed Scopus Google Scholar), a that the of and the to interact with Rab4 and Rab11. J. A. G. and M. W. have been to the of this to contains of work was in the homologue of was to the number J. A. Shibata K. 2001; PubMed Scopus Google Scholar). the to the identified the of of the of We identified that the RCP, and acid that RCP is a predominantly protein with a and two coiled-coil and of the identified and as of work was in of as well as a in R. J. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. R. J. L.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). in the the are in the name in each An of RCP with proteins is shown their RCP and with and respectively. the of between proteins their of proteins a or in their and all a Rab coiled-coil their of acid of of the acid of RCP with and the of coiled-coil the A. 1996; PubMed Google Scholar). The number is along the and the is the the and coiled-coil in RCP and the of the and Rip11 has been as a of membrane trafficking the recycling compartment R. J. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The and of the have been as proteins to the endosomal recycling compartment in and proteins a number of RCP is the to interact with RCP is therefore a of a of proteins that interact with Rab4 and function along the endosomal recycling pathway. We the expression of RCP by a as the from a of tissues and RCP to a of known to RCP of the from all tissues the of of RCP in for a control as in to a the function and localization of RCP, was expressed and identified a protein with of in all cell lines tested. The RCP was a mammalian expression and expressed in The of the protein to that of RCP of cells and that RCP is a predominantly protein We the of RCP membrane by and RCP was by it was by 1 or The localization of the and was as the described that the expression of RCP, both by and to be in all cell tested. Furthermore, RCP 80-kDa protein that is predominantly and is to and is from membranes by The of the yeast two-hybrid that interacts with Rab4 and Rab11 expressed in E. was by and to The with or as a the by and with a to the of Furthermore, as the carboxyl-terminal region of RCP interact and with Rab4 and Rab11 in the function of RCP, the localization of RCP in cells by It a in the that colocalizes with the in the region of the cell the Rab4 Rab4 by RCP localization with Rab4, a described cell A. R. K. McCaffrey Biochem. 2001; PubMed Scopus Google Scholar). RCP with in the with Rab11 was with the RCP is also cells with RCP was with a the The protein was expressed a such that the RCP We with Rab11. Furthermore, is Rab11 is to be or the RCP with a found late endosomes a of the 1998; PubMed Scopus Google Scholar, T. E. P. Parton R.G. Gruenberg J. 1998; PubMed Scopus Google Scholar) We also the localization of with early endosome-associated antigen 1 by and that two markers is a Rab5 protein that to to the recycling compartment (11.Sonnichsen B. De Renzis S. Nielsen E. Rietdorf J. Zerial M. J. Cell Biol. 2000; 149: 901-914Crossref PubMed Scopus (820) Google Scholar, M. Stoorvogel W. Ullrich O. J. Cell Sci. 1999; 112: 4773-4783Crossref PubMed Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). RCP and it is likely that RCP is to a effects of the early endosomal cells with a that this RCP the cells to Tfn in the the in endosomal in the of the as well as to vesicles cells the of the Tfn compartment membrane that the which this a it is to membranes is likely to be it is in a with to Rab4 Rab11 by in a their with It is to that the Tfn compartment expression is to that the mutant is expressed (10.Wilcke M. Johannes L. Galli T. Mayau V. Goud B. Salamero J. J. Cell Biol. 2000; 151: 1207-1220Crossref PubMed Scopus (322) Google Scholar). the of the Tfn the by for or uptake by a for of endosomal from endosomes. cells by the was a compartment the are to it is likely that endosomal recycling compartment. Rab11 also transport to the the localization of in cells or is a that between the plasma membrane and the (10.Wilcke M. Johannes L. Galli T. Mayau V. Goud B. Salamero J. J. Cell Biol. 2000; 151: 1207-1220Crossref PubMed Scopus (322) Google Scholar), a of to the the transferrin receptor already expression early endosomal of that by (10.Wilcke M. Johannes L. Galli T. Mayau V. Goud B. Salamero J. J. Cell Biol. 2000; 151: 1207-1220Crossref PubMed Scopus (322) Google Scholar). this in in the tubulation of the Tfn compartment be by or Rab11. We this by with or and cells to cells that and the Tfn compartment was This is with the that Rab11 in a and the of Rab11 this We also the of with Rab4 or Rab4 function to tubulation of the Tfn compartment (7.McCaffrey M. Bielli A. Cantalupo G. Mora S. Roberti V. Santillo M. Drummond F. Bucci C. FEBS Lett. 2001; 495: 21-30Crossref PubMed Scopus (141) Google Scholar). as of with Rab4 or also in tubulation of the Tfn compartment the that or RCP has the of the receptor recycling the trafficking of was cells with or RCP and the with was and the cells to and the ligand The in the and therefore was and in each to the of Tfn in control cells with the Overexpression of in a dramatic in the of recycling RCP recycling with the Rab4, also recycling to a specifically the effects recycling from the the was to the of the to be (8.Ullrich O. Reinsch S. Urbe S. Zerial M. Parton R.G. J. Cell Biol. 1996; 135: 913-924Crossref PubMed Scopus (1098) Google Scholar). cells with the transferrin receptor and the with for ligand was and the cells for a This the Tfn the to cycle of the cell and the Tfn trafficking along the to the the the of in the was various Overexpression of in a of recycling from the RCP a of recycling also as (8.Ullrich O. Reinsch S. Urbe S. Zerial M. Parton R.G. J. Cell Biol. 1996; 135: 913-924Crossref PubMed Scopus (1098) Google Scholar), to a Furthermore, Rab4 affects late endosomal trafficking (7.McCaffrey M. Bielli A. Cantalupo G. Mora S. Roberti V. Santillo M. Drummond F. Bucci C. FEBS Lett. 2001; 495: 21-30Crossref PubMed Scopus (141) Google Scholar) as well as recycling (5.van der Sluijs P. Hull M. Webster P. Male P. Goud B. Mellman I. Cell. 1992; 70: 729-740Abstract Full Text PDF PubMed Scopus (520) Google Scholar), RCP also play a role in transport along the pathway. Overexpression of the uptake or degradation of recycling the from the quantitative that RCP in endosomal likely the Rab proteins a role in the of transport the of the it is known that are Rab proteins 2001; PubMed Scopus Google Scholar), and it is that each controls a specific in a transport pathway. The receptor recycling is the control of including Rab4, and which function in a The that Rab5 controls transport from the plasma membrane and early endosomal Rab4 transport from the sorting and Rab11 transport the recycling compartment. the and of Rab coupling a novel protein that interacts with both Rab4 and Rab11. We that the of RCP are for Rab4 and Rab11 The is strongly with RCP interacting with the of Furthermore, the with Rab4 is the a in The with Rab11 in that the and that of RCP with the is the Rab11 state. RCP is to a that has been in and D. J.P. W. J. 1999; PubMed Scopus Google Scholar). work was in a from and R. J. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) as a Rab11-interacting protein that in the of membrane work from two has described other of this of proteins various or proteins R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) and interacting proteins R. D. R. J. L.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). RCP is recently described proteins and is therefore a of this novel protein family. that RCP colocalizes with a small of Rab4, is with Rab11. Additionally, is with this that RCP is predominantly protein is likely to interact with the of Rab4 that is for transport to this compartment. Furthermore, of of RCP the Rab results in the of network that be with to be from the recycling compartment they are to Tfn This is to that of the mutant of (10.Wilcke M. Johannes L. Galli T. Mayau V. Goud B. Salamero J. J. Cell Biol. 2000; 151: 1207-1220Crossref PubMed Scopus (322) Google Scholar). as the between RCP and Rab11 the it is likely that a Rab11 by Rab11. with this expression of Rab11 the that the tubulation is as a of Rab11 in a RCP is the of a protein that interacts with interacts with both Rab5 and Rab4 (20.Vitale G. Rybin V. Christoforidis S. Thornqvist P. McCaffrey M. Stenmark H. Zerial M. EMBO J. 1998; 17: 1941-1951Crossref PubMed Scopus (197) Google Scholar). Rab4 Rab5 in early endosomal it is that rabaptin as intermediate between two proteins. it is that RCP is intermediate between Rab4 and Rab11 Rab4 in the recycling pathway. Rab11 to function trafficking the Rab4, the other the of the sorting and affects both recycling and degradation (7.McCaffrey M. Bielli A. Cantalupo G. Mora S. Roberti V. Santillo M. Drummond F. Bucci C. FEBS Lett. 2001; 495: 21-30Crossref PubMed Scopus (141) Google Scholar), by interacting with of number of Rab4 effectors have already been such as rabaptin (20.Vitale G. Rybin V. Christoforidis S. Thornqvist P. McCaffrey M. Stenmark H. Zerial M. EMBO J. 1998; 17: 1941-1951Crossref PubMed Scopus (197) Google Scholar), rabaptin 4 (21.Nagelkerken B. Van Anken E. Van Raak M. Gerez L. Mohrmann K. Van Uden N. Holthuizen J. Pelkmans L. Van Der Sluijs P. Biochem. J. 2000; 3: 593-601Crossref Google Scholar), syntaxin 4 (22.Li L. Omata W. Kojima I. Shibata H. J. Biol. Chem. 2001; 276: 5265-5273Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar), Rab4-interacting protein (Rab4ip) (23.Cormont M. Mari M. Galmiche A. Hofman P. Le Marchand-Brustel Y. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1637-1642Crossref PubMed Scopus (88) Google Scholar), and the dynein light intermediate A. R. K. McCaffrey Biochem. 2001; PubMed Scopus Google Scholar). quantitative that RCP in the endosomal recycling process and is involved in the late endosomal pathway. Overexpression of the region of RCP, which contains the Rab4 and Rab11 results in a that this of ligand that the of recycling specifically from the that the RCP mutant recycling from this compartment. This was that with the Rab This be to the of the of Rab4 and Rab11 in the that the RCP mutant also other of the Rab11 family. RCP, as a predominantly be involved in the of a Rab4- or to the compartment. Considering the localization of RCP, which predominantly the suggest that it as a for Rab4 vesicles the is that RCP interacts with Rab4 a sorting and in trafficking or the RCP to Rab11 the membrane interact with Rab11 already with the or are the membrane localization of Rab11 with of be necessary to It also be important to the to RCP membrane localization as well as it subsequently to this be of Rabs are involved in this process and the role of the RCP in The of RCP as interacting of Rab4 and with to and the R. J. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. R. J. L.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), to of the Furthermore, the between the network and the network to or the endosomal both in of their as well as by their with of to the of such and to the of this novel protein be crucial of the process of endosomal and with to the by the Rab We M. Zerial and P. Chavrier for the of Rab5 and Rab7 A. for and for the of the J. Gruenberg for the acid D. for and the for