David S. Cafiso, PhD
Protein recruitment to membrane and cell signaling (Ras signaling and cancer)
Work in the Cafiso laboratory is directed at studying membranes and membrane proteins, and there are currently two general areas of research ongoing. One area of investigation involves studies on the mechanisms by which proteins become attached to membrane surfaces, and a second area is directed at the molecular mechanisms of membrane transport. They are determining the structures of proteins and protein domains that function in membrane binding, and are characterizing the forces and mechanisms that lead to membrane attachment. These include domains such as C2, PH and ENTH domains that function to specifically attach proteins to the membrane interface in response to signals such as Ca2+ and polyphosphoinositols. They are also characterizing proteins such as MARCKS (the myristoylated alanine rich C-kinase substrate) which regulates polyphosphoinositols, such as PI(4,5)P2, by sequestering the lipid laterally into domains.
A second area of investigation involves membrane transport. They are currently investigating the molecular mechanisms that function to transport solutes across lipid bilayers. For example, in gram negative bacteria, such as E. coli, they are examining the molecular mechanisms by which vitamin B-12 is transported across both the outer and inner bacterial membranes. They are investigating the molecular mechanisms of transport in BtuC/D, a transporter that belongs to the large family of ABC cassette transporters.
Work in both these areas is critical to an understanding of the mechanisms that underlie cell transformation and cancer. The mechanisms leading to the attachment of proteins to membranes are critical for cell-signaling and cancer because they control protein-protein interactions and the access of enzymes to lipid substrates. For example the oncogenic form of the src tyrosine kinase (pp60v-src) is not active and fails to transform cells until it becomes localized to the plasma membrane interface. Translocation of Ras to the membrane interface is also a key to cell transformation by the oncogenic forms of Ras. Work that they are carrying out on BtuC/D will aid in understanding the molecular mechanisms of action of this protein family, which include transporters that function in the multidrug resistance of cancer cells.