TRANSFORMING GROWTH-FACTOR-ALPHA AND BETA-AMYLOID PRECURSOR PROTEIN SHARE A SECRETORY MECHANISM

被引:133
作者
ARRIBAS, J
MASSAGUE, J
机构
[1] MEM SLOAN KETTERING CANC CTR,CELL BIOL & GENET PROGRAM,NEW YORK,NY 10021
[2] MEM SLOAN KETTERING CANC CTR,HOWARD HUGHES MED INST,NEW YORK,NY 10021
关键词
D O I
10.1083/jcb.128.3.433
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor alpha (TGF-alpha). The defect in TGF-alpha cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF alpha cleavage in wild-type cells. The mutant clones do not have defects in TFG-alpha expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-alpha cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include beta-amyloid precursor protein (beta-APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A beta, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC-dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function.
引用
收藏
页码:433 / 441
页数:9
相关论文
共 41 条
  • [1] THE CYTOPLASMIC CARBOXY-TERMINAL AMINO-ACID SPECIFIES CLEAVAGE OF MEMBRANE TGF-ALPHA INTO SOLUBLE GROWTH-FACTOR
    BOSENBERG, MW
    PANDIELLA, A
    MASSAGUE, J
    [J]. CELL, 1992, 71 (07) : 1157 - 1165
  • [2] ACTIVATED RELEASE OF MEMBRANE-ANCHORED TGF-ALPHA IN THE ABSENCE OF CYTOSOL
    BOSENBERG, MW
    PANDIELLA, A
    MASSAGUE, J
    [J]. JOURNAL OF CELL BIOLOGY, 1993, 122 (01) : 95 - 101
  • [3] PROCESSING OF ALZHEIMER BETA-A4 AMYLOID PRECURSOR PROTEIN - MODULATION BY AGENTS THAT REGULATE PROTEIN-PHOSPHORYLATION
    BUXBAUM, JD
    GANDY, SE
    CICCHETTI, P
    EHRLICH, ME
    CZERNIK, AJ
    FRACASSO, RP
    RAMABHADRAN, TV
    UNTERBECK, AJ
    GREENGARD, P
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (15) : 6003 - 6006
  • [4] CALCIUM REGULATES PROCESSING OF THE ALZHEIMER AMYLOID PROTEIN-PRECURSOR IN A PROTEIN-KINASE C-INDEPENDENT MANNER
    BUXBAUM, JD
    RUEFLI, AA
    PARKER, CA
    CYPESS, AM
    GREENGARD, P
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) : 4489 - 4493
  • [5] STUDY OF THE SYNTHESIS AND SECRETION OF NORMAL AND ARTIFICIAL MUTANTS OF MURINE AMYLOID PRECURSOR PROTEIN (APP) - CLEAVAGE OF APP OCCURS IN A LATE COMPARTMENT OF THE DEFAULT SECRETION PATHWAY
    DESTROOPER, B
    UMANS, L
    VANLEUVEN, F
    VANDENBERGHE, H
    [J]. JOURNAL OF CELL BIOLOGY, 1993, 121 (02) : 295 - 304
  • [6] LIGAND AND PROTEIN KINASE-C DOWNMODULATE THE COLONY-STIMULATING FACTOR-I RECEPTOR BY INDEPENDENT MECHANISMS
    DOWNING, JR
    ROUSSEL, MF
    SHERR, CJ
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1989, 9 (07) : 2890 - 2896
  • [7] MEMBRANE-PROTEINS WITH SOLUBLE COUNTERPARTS - ROLE OF PROTEOLYSIS IN THE RELEASE OF TRANSMEMBRANE PROTEINS
    EHLERS, MRW
    RIORDAN, JF
    [J]. BIOCHEMISTRY, 1991, 30 (42) : 10065 - 10074
  • [8] CLEAVAGE OF AMYLOID-BETA PEPTIDE DURING CONSTITUTIVE PROCESSING OF ITS PRECURSOR
    ESCH, FS
    KEIM, PS
    BEATTIE, EC
    BLACHER, RW
    CULWELL, AR
    OLTERSDORF, T
    MCCLURE, D
    WARD, PJ
    [J]. SCIENCE, 1990, 248 (4959) : 1122 - 1124
  • [9] SOLUBLE CYTOKINE RECEPTORS - THEIR ROLE IN IMMUNOREGULATION
    FERNANDEZBOTRAN, R
    [J]. FASEB JOURNAL, 1991, 5 (11) : 2567 - 2574
  • [10] TRANSMEMBRANE FORM OF THE KIT LIGAND GROWTH-FACTOR IS DETERMINED BY ALTERNATIVE SPLICING AND IS MISSING IN THE SI(D) MUTANT
    FLANAGAN, JG
    CHAN, DC
    LEDER, P
    [J]. CELL, 1991, 64 (05) : 1025 - 1035