Attenuation of cell adhesion in lymphocytes is regulated by CYTIP, a protein which mediates signal complex sequestration.
An important theme in molecular cell biology is the regulation of protein recruitment to the plasma membrane. Fundamental biological processes such as proliferation, differentiation or leukocyte functions are initiated and controlled through the reversible binding of signaling proteins to phosphorylated membrane components. This is mediated by specialized interaction modules, such as SH2 and PH domains. Cytohesin-1 is an intracellular guanine nucleotide exchange factor, which regulates leukocyte adhesion. The activity of cytohesin-1 is controlled by phospho inositide-dependent membrane recruitment. An interacting protein was identified, the expression of which is upregulated by cytokines in hematopoietic cells. This molecule, CYTIP, is also recruited to the cell cortex by integrin signaling via its PDZ domain. However, stimulation of Jurkat cells with phorbol ester results in re-localization of CYTIP to the cytoplasm, and membrane detachment of cytohesin-1 strictly requires co-expression of CYTIP. Consequently, stimulated adhesion of Jurkat cells to intracellular adhesion molecule-1 is repressed by CYTIP. These findings outline a novel mechanism of signal chain abrogation through sequestration of a limiting component by specific protein-protein interactions.
Boehm
Thomas
T
Laboratory for Molecular Biology, Gene Center, University of Munich, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany.
Hofer
Susanne
S
Winklehner
Patricia
P
Kellersch
Bettina
B
Geiger
Christiane
C
Trockenbacher
Alexander
A
Neyer
Susanne
S
Fiegl
Heidi
H
Ebner
Susanne
S
Ivarsson
Lennart
L
Schneider
Rainer
R
Kremmer
Elisabeth
E
Heufler
Christine
C
Kolanus
Waldemar
W
D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D001392:Azocines; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019169:Jurkat Cells; D018613:Microscopy, Confocal; D010703:Phorbol Esters / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011807:Quinolizines; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D020798:Two-Hybrid System Techniques; D000093843:Quinolizidine Alkaloids
D000255:Adenosine Triphosphate; D000470:Alkaloids; D001392:Azocines; D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; D018799:Intercellular Adhesion Molecule-1; D010703:Phorbol Esters; D011807:Quinolizines; D014157:Transcription Factors; C084539:CYTIP protein, human; C100723:cytohesin-1; C004712:cytisine; D000093843:Quinolizidine Alkaloids