Abstract
Kindlins are FERM-containing cytoplasmic proteins that regulate integrin-mediated cell-cell and cell-extracellular matrix (ECM) attachments. Kindlin-3 is expressed in hematopoietic cells, platelets, and endothelial cells. Studies have shown that kindlin-3 stabilizes cell adhesion mediated by ß1, ß2, and ß3 integrins. Apart from integrin cytoplasmic tails, kindlins are known to interact with other cytoplasmic proteins. Here we demonstrate that kindlin-3 can associate with ribosome via the receptor for activated-C kinase 1 (RACK1) scaffold protein based on immunoprecipitation, ribosome binding, and proximity ligation assays. We show that kindlin-3 regulates c-Myc protein expression in the human chronic myeloid leukemia cell line K562. Cell proliferation was reduced following siRNA reduction of kindlin-3 expression and a significant reduction in tumor mass was observed in xenograft experiments. Mechanistically, kindlin-3 is involved in integrin α5ß1-Akt-mTOR-p70S6K signaling; however, its regulation of c-Myc protein expression could be independent of this signaling axis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibiotics, Antineoplastic / pharmacology
-
Cell Proliferation / drug effects
-
GTP-Binding Proteins / metabolism
-
HEK293 Cells
-
Human Umbilical Vein Endothelial Cells
-
Humans
-
Integrin beta3 / metabolism
-
K562 Cells
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
-
Membrane Proteins / antagonists & inhibitors
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Mice
-
Mice, Inbred BALB C
-
Mice, Knockout
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism*
-
Protein Binding
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / metabolism*
-
RNA Interference
-
Receptors for Activated C Kinase
-
Receptors, Cell Surface / metabolism
-
Recombinant Proteins / biosynthesis
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / isolation & purification
-
Ribosomes / metabolism*
-
Signal Transduction / drug effects
-
Sirolimus / pharmacology
-
TOR Serine-Threonine Kinases / metabolism
Substances
-
Antibiotics, Antineoplastic
-
FERMT3 protein, human
-
Integrin beta3
-
Membrane Proteins
-
Neoplasm Proteins
-
Proto-Oncogene Proteins c-myc
-
RACK1 protein, human
-
Receptors for Activated C Kinase
-
Receptors, Cell Surface
-
Recombinant Proteins
-
TOR Serine-Threonine Kinases
-
GTP-Binding Proteins
-
Sirolimus