Faculty: Richard Anderson, PhD
|Contact:|| 3750 MSC |
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:
- 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.
- 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.
The laboratory uses cutting edge techniques including 1) cell culture, 2) videomicroscopy of cells and molecular dynamics of proteins within living cells, 3) 3-D structure-function analysis, 4) expression of genes with functionally targeted mutations, 5) microarray analysis of gene expression, 6) knock out techniques, 7) molecular genetic analysis of gene expression, and 8) molecular biological approaches to analyze for analysis of signal transduction mechanisms.
Research Scientists in the Anderson Laboratory:
- Dr. Weimin Li, M.D., Ph.D., Postdoc (Ph.D. - Biochemistry, University Basel, Switzerland)
- 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)
- Suyong Choi
- Xiaojun Tan
Associate Research Specialist: Position Open
- Diana Civitello
- Andrew Krismer
- Yihan Liao
Honors & Awards
- 2005 - Kellett Mid-Career Award
- Sigma Xi Graduate Research Award
- NIH Postdoctoral Fellowship
- American Cancer Society Postdoctoral Fellowship
- Bacaner Basic Science Award
- Sun Y, Hedman AC, Tan X, Anderson RA. (2013) An unexpected role for PI4,5P 2 in EGF receptor endosomal trafficking. Cell Cycle. 2013 Jul 1;12(13):1991-2. doi: 10.4161/cc.25309. Epub 2013 Jun 10. No abstract available. PMID: 23759577 [PubMed - in process]
- Li W, Laishram RS, Ji Z, Barlow CA, Tian B, and Anderson RA (2012). Star-PAP Control of BIK Expression and Apoptosis Is Regulated by Nuclear PIPKI ± and PKC ¥ Signaling. Mol Cell. 45(1):25-37. PMID: 22244330
- Thapa N, Sun Y, Schramp M, Choi S, Ling K, and Anderson RA (2012). Phosphoinositide signaling regulates the exocyst complex and polarized integrin trafficking in directionally migrating cells. Dev Cell. 116-30. PMID: 22264730
- Schramp M, Hedman A, Li W, Tan X,and Anderson R. (2012) PIP Kinases from the Cell Membrane to the Nucleus. Subcell Biochem. 58:25-59. PMID: 22403073
- Laishram RS, Barlow CA, and Anderson RA. (2011). CKI isoforms ± and µ regulate Star-PAP target messages by controlling Star-PAP poly(A) polymerase activity and phosphoinositide stimulation. Nucleic Acids Res. 39:7961-73. PMID: 21729869
- Laishram RS and Anderson RA. (2010). The poly A polymerase Star-PAP controls 3'-end cleavage by promoting CPSF interaction and specificity toward the pre-mRNA. EMBO J. 29(24):4132-45. PMID: 21102410
- Sun Y, Turbin DA, Ling K, Thapa N, Leung S, Huntsman DG, and Anderson RA. (2010). Type I gamma phosphatidylinositol phosphate kinase modulates invasion and proliferation and its expression correlates with poor prognosis in breast cancer. Breast Cancer Res. 12(1):R6. PMID: 20074374
- Schill NJ and Anderson RA. (2009). Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. Biochem J. 422(3):473-82. PMID: 19548880
- Mellman DL, Anderson RA (2009). A novel gene expression pathway regulated by nuclear phosphoinositides. Adv Enzyme Regul. 49(1):11-28. PMID: 19534024
- 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.