Richard A. Anderson, Ph.D. Director Molecular and Cellular Pharmacology Program Professor Department of Pharmacology raanders@wisc.edu

Research Interests: Signal Transduction Mechanisms that control cellular functions and disease

Our major research focus has the objective of understanding phosphoinositide (PI) and inositol phosphate signal transduction pathways that impact cellular regulatory events. All eukaryotic cells are regulated by phosphoinositide signals. In phosphoinositide signaling, PI, a phospholipid, is sequentially phosphorylated on the inositol ring to form essential signaling molecules such phosphatidylinositol-4,5-bisphosphate (PI4,5P2). PI4,5P2 is directly synthesized by phosphatidylinositol-phosphate kinases (PIPKs), and PI4,5P2 occupies an essential position in PI signaling by directly regulating cellular functions that include cell proliferation, secretion, cytoskeletal assembly and cell motility. In addition, PI4,5P2 is a key transducer of cellular signals as a precursor for many second messengers. The PIPKs define an enzyme superfamily responsible for the generation of all PI derived second messengers, demonstrating that these kinases have roles in many cellular functions. The different PIPK family members are targeted to subcellular compartments by specific protein-protein interactions. The interactions between the PIPKs and targeting proteins results in spatial and temporal generation of PI4,5P2 that regulates specific cellular functions.

The laboratory focuses on two broad topics: 

1) Signaling mechanisms that control epithelial cancer metastasis- The metastasis of cancers of epithelial origin (~75% of all human cancers) progress through two stages: 1) loss of epithelial polarity and cell-cell contacts, called the epithelial to mesenchymal transition (EMT), and 2) development of a migratory phenotype with the resulting migration of tumor cells to the vasculature or lymph system where they can move to different parts of the body. 

We have shown that a PIPK (PIPKIg) is required for the assembly of E-cadherin based cell-cell contacts. E-cadherin complex assembly is a key event, as the loss of these cell-cell contacts is a hallmark of cancer progression and is required for the metastasis of epithelial cancers. Upon loss of E-cadherin, cells migrate to the vasculature a process driven by cytokines. This migratory process is also dependent upon PIPKIg. We have defined aspects of the molecular basis for PIPKIg regulation of cell-cell contacts and migration, and have evidence that PIPKIg plays a role in the progression of human breast cancers.  Many mechanistic aspects remain to be defined.

2) Nuclear phosphoinositide signaling controls gene expression. Within nuclei, we have discovered a unique phosphoinositide signaling pathway that modulates the expression of a set of genes that play roles in Alzheimer’s disease, cardiovascular disease and cancer. In elucidating the underlying mechanism for this regulation, we have discovered a novel poly(A) polymerase that is activated by phosphoinositide messengers. Poly(A) polymerase regulates the expression of specific messenger RNAs by adding a 3’-end poly(A) tail that is required for nuclear export and efficient translation. The mechanism of how this poly(A) polymerase is regulated, as well as the elucidation of other nuclear pathways regulated by phosphoinositides will be the continuing focus.

Research Scientists in the Anderson Laboratory

• Professor Chang Ho Lee, Ph.D., Visiting Professor (Ph.D. - University of Wisconsin)
• Dr. Kun Ling, Ph.D., Scientist (Ph.D. - Molecular Biology, Institute of Cell Biology, Shanghai)
• Dr. Weimin Li, M.D., Ph.D., Postdoc (Ph.D. - Biochemistry, University Basel, Switzerland)
• Dr. Christy Barlow, Ph.D. Postdoc (Ph.D. - Molecular Biology, University of Vermont)
• Dr. Yue Sun, Ph.D. Postdoc (Ph.D. - Molecular Biology, Institute of Cell Biology, Shanghai)
• Narendra Thapa, Ph.D. Postdoc (Ph.D. - 2006, Kyungpook National University, Republic of Korea)
• L. Rakesh Singh, Ph.D. Postdoc (Ph.D. - Centre for DNA Fingerprinting and Diagnostics, Indian Institute of Science, Hyderabad, India)
• Mark Schramp, Ph.D. Postdoc (Ph.D. - Molecular Biology, University of California, Berkely)

Graduate Students:

• Andrew Hedman (B.S. - University of Illinois)
• Matthew Bunce (B.S. - University of Virginia)
• David Mellman (B.S. - University of Colorado)
• Nicholas Schill (B.S. - St. Norbert College)
• Jessica Heck (B.S. - University of Minnesota)

Associate Research Specialist: Position Open

Research Assistants:

• Kristin Mueller
• Lisa Christenson
• Lisa Goetter

Positions available:

• Postdoctoral and Graduate Student positions are available for Fall 2008

• Gonzales ML, Mellman DL, and Anderson RA. (2008). Star-PAP is Associated with and Phosphorylated by the Protein Kinase CKIa that is also Required for Expression of Select Star-PAP Target Messenger RNA. J Biol Chem. 283:12665-73.

• Mellman DL, Gonzales ML, Song C, Barlow C, Wang P, Kendziorski C, and Anderson RA. (2008). A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs. Nature. 451:1013-1017.
  

• Sun Y, Wagoner MP, Ling K, and Anderson RA. (2007). Type Ig PIP Kinase is Required for EGF-Stimulated Directional Cell Migration. J Cell Biol. In Press.
  
  
• Heck JN, Mellman DL, Ling K, Sun Y, Wagoner MP, Schill NJ, and Anderson RA. (2007). A conspicuous connection: structure defines function for the phosphatidylinositol-phosphate kinase family. Crit Rev. Biochem Mol Biol. 42:15-39. PDF PMID 17364683
  
  
• Ling K, Bairstow SF, Carbonara C, Turbin DA, Huntsman DG, and Anderson RA. (2007). Type Ig phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with m1B adaptin. J Cell Biol. 176:343-53. PDF PMID 17261850
  
  
• Ling K, Schill N, Wagoner M, Sun Y, and Anderson RA. (2006). Movin’ on up: PI4,5P2’s role in cell migration. Trends Cell Biology. 16:276-84.
  
  
• Bairstow SF, Ling K, and Anderson RA. (2005). Type Ig phosphatidylinositol phosphate kinase associates with regulates the SHP-1 tyrosine phosphatase. J Biol Chem. 280:23884-23891
  
  
• Ling K, Doughman RL, Iyer VV, Firestone AJ, Bairstow SF, Mosher DF, Schaller MD, and Anderson RA. (2003). Tyrosine phosphorylation of type Ig phosphatidylinositol phosphate kinase by Src regulates an integrin/talin switch. J Cell Biol. 163:1339-1349.
  
  
• Ling K, Doughman RL, Firestone AJ, Bunce MW, and Anderson RA. (2002). Type Ig phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature. 420:89-93.
  
  
• Kunz J, Wilson MP, Hurley JH, Majerus PW, and Anderson RA. (2000). The activation loop of phosphatidylinositol phosphate kinases determines signaling specificity. Mol Cell. 5:1-11.
  
  
• Rao VD, Misra S, Boronenkov IV, Anderson RA, and Hurley JH. (1998). Structure of the type IIb phosphatidylinositol phosphate kinase: A protein kinase fold flattened for interfacial phosphorylation. Cell. 94:829-839.

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