Lab Website: https://medicine.uiowa.edu/pharmacology/profile/songhai-chen

GPCR and G protein signaling in leukocyte migration and tumor metastasis

Our research focuses on defining the function and signaling mechanisms of heterotrimeric G proteins, in particular G protein βγ subunits, in leukocyte migration and tumor metastasis. Heterotrimeric G proteins are composed of three subunits, Gα, Gβ and Gγ, each of which includes multiple isoforms (at least 23 Gα, 6 Gβ and 12 Gγ). Gβ and Gγ subunits form an obligated dimer, Gβγ, and like the Gα subunit, can transmit signals from G protein-coupled receptors (GPCRs) to mediate diverse cellular functions, ranging from the physiological functions of immune cells to the pathological process of tumor metastasis. In recent years, the major focus of our research is to elucidate how Gβγ subunits orchestrate a signaling network to promote leukocyte migration. Particularly, we are interested in understanding how Gβγ signaling is regulated by a group of novel interacting proteins, WD40 repeat-containing proteins. Our studies involve multidisciplinary approaches including the use of biochemical, biophysical and molecular biological characterizations and model systems such as zebrafish and mice. Our recent findings suggest that two WD40 repeat-containing proteins, WDR26 and RACK1, act as positive and negative regulators of Gβγ signaling, and that alternate interactions of these two proteins with Gβγ control the signaling flow of Gβγ to regulate leukocyte polarization and migration. Importantly, we also found that aberrant regulation of Gβγsignaling by WD40 proteins contributes to tumorigenesis and metastasis of breast and prostate cancers.

A second line of investigation has been uncovering the role of Gβγ signaling in the regulation of tumor growth and metastasis. Aberrant activation of GPCRs has been shown to be involved in every step of tumor progression. Our studies have revealed that Gβγ serves as a point of signal convergence for multiple GPCRs that promote tumor growth, and in particular, metastatic spread of tumors to distant organs. Our current research is to elucidate the molecular mechanisms by which Gβγ mediates the crosstalk between the tumor microenvironment, tumor cells, and the sensory neurons that promote bone metastasis and the perception of chronic bone pain. We are also exploring the potential of targeting Gβγ signaling with small molecules for the therapeutics of breast and prostate tumors.

PubMed link

Department/Program Affiliations:
Molecular Medicine
Neuroscience and Pharmacology