Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration-proliferation dichotomy.
Signals propagated by receptor tyrosine kinases (RTKs) can drive cell migration and proliferation, two cellular processes that do not occur simultaneously--a phenomenon called "migration-proliferation dichotomy." We previously showed that epidermal growth factor (EGF) signaling is skewed to favor migration over proliferation via noncanonical transactivation of Gαi proteins by the guanine exchange factor (GEF) GIV. However, what turns on GIV-GEF downstream of growth factor RTKs remained unknown. Here we reveal the molecular mechanism by which phosphorylation of GIV by cyclin-dependent kinase 5 (CDK5) triggers GIV's ability to bind and activate Gαi in response to growth factors and modulate downstream signals to establish a dichotomy between migration and proliferation. We show that CDK5 binds and phosphorylates GIV at Ser1674 near its GEF motif. When Ser1674 is phosphorylated, GIV activates Gαi and enhances promigratory Akt signals. Phosphorylated GIV also binds Gαs and enhances endosomal maturation, which shortens the transit time of EGFR through early endosomes, thereby limiting mitogenic MAPK signals. Consequently, this phosphoevent triggers cells to preferentially migrate during wound healing and transmigration of cancer cells. When Ser1674 cannot be phosphorylated, GIV cannot bind either Gαi or Gαs, Akt signaling is suppressed, mitogenic signals are enhanced due to delayed transit time of EGFR through early endosomes, and cells preferentially proliferate. These results illuminate how GIV-GEF is turned on upon receptor activation, adds GIV to the repertoire of CDK5 substrates, and defines a mechanism by which this unusual CDK orchestrates migration-proliferation dichotomy during cancer invasion, wound healing, and development.
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651; Department of Chemistry and Biochemistry, California State University Long Beach, Long Beach, CA 90840-9507; prghosh@ucsd.edu deepali.bhandari@csulb.edu mfarquhar@ucsd.edu.
Deepali
D
Bhandari
Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0651;
Inmaculada
I
Lopez-Sanchez
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651;
Andrew
A
To
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651;
I-Chung
IC
Lo
Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0651;
Nicolas
N
Aznar
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
Anthony
A
Leyme
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651;
Vijay
V
Gupta
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651;
Ingrid
I
Niesman
Department of Chemistry and Biochemistry, California State University Long Beach, Long Beach, CA 90840-9507;
Adam L
AL
Maddox
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
Mikel
M
Garcia-Marcos
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651; prghosh@ucsd.edu deepali.bhandari@csulb.edu mfarquhar@ucsd.edu.
Marilyn G
MG
Farquhar
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651; Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0651; prghosh@ucsd.edu deepali.bhandari@csulb.edu mfarquhar@ucsd.edu.
Pradipta
P
Ghosh
D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009024:Morphogenesis; D010766:Phosphorylation; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D014945:Wound Healing
C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D066246:ErbB Receptors; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human
GIV/Girdin; growth factor receptor tyrosine kinase; guanine nucleotide exchange factor; heterotrimeric G protein; migration–proliferation dichotomy