Association of PI 3-K with tyrosine phosphorylated Vav is essential for its activity in neutrophil-like maturation of myeloid cells.
The importance of the Vav family of signal transduction molecules in hematopoietic cells has long been acknowledged, even though its role and its regulatory mechanism are not completely understood. We have previously demonstrated that tyrosine-phosphorylated Vav, also located inside the nucleus of myeloid cells, is up-regulated during maturation of promyelocytic precursors induced by all-trans-retinoic acid (ATRA). Here, we report that the tyrosine phosphorylation of Vav during granulocytic maturation is dependent on the tyrosine kinase Syk and is essential for the morphological changes of the cell nucleus. These ATRA-induced events are independent on the guanine nucleotide exchange activity of Vav. We also found that, in differentiating cells, and in both cytoplasmic and nuclear compartments, tyrosine phosphorylated Vav associates with the regulatory subunit of phosphoinositide 3-kinase (PI 3-K). The Vav/p85 interaction is essential for the ATRA-induced PI 3-K activity and for association of PI 3-K with actin, particularly in the nucleus. Our data indicate an unprecedented crucial function for Vav in modulating the morphological maturation process of myeloid cells in a GDP-GTP exchange factor (GEF)-independent manner and suggest a role of Vav as an adaptor protein responsible of targeting PI 3-K to its intranuclear substrates.
Bertagnolo
Valeria
V
Signal Transduction Unit, Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy.
Brugnoli
Federica
F
Marchisio
Marco
M
Celeghini
Claudio
C
Carini
Cinzia
C
Capitani
Silvano
S
D000199:Actins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase; D014212:Tretinoin / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism*
D000199:Actins; D018797:Cell Cycle Proteins; D004792:Enzyme Precursors; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D014443:Tyrosine; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase