Professor, Biochemistry and Molecular Biology, and Eppley Institute, Chair, Graduate Committee
Phone: 402-559-7824 (Office)
Ph.D., University of Vermont, 1981
Student research opportunities in my lab:
Medical students, summer research
Undergraduate students, summer research
Primary Research/Clinical Interests/Expertise:
Biochemical Markers; Biochemistry; Biochemistry, Proteins; Biology, Cellular; Biology, Developmental/Evolutionary; Cancer/Carcinogenesis; Chemotherapeutic Agents; Computer Graphics; Diabetes; Disease Model; Instrumentation, Scientific; Perinatal Disorders; Receptors
Major interests in signal transduction/biological effects of the insulin-like growth factors with emphasis on structure-function relationships of the IGF-II/mannose 6-phosphate receptor. Main current projects involve investigation of the IGF axis in prostate cancer and analysis of the contributions of the various ligand-binding functions of the IGF-II/mannose 6-phosphate receptor to its growth suppressor/tumor suppressor activity. The long-range goal is to improve understanding of this receptor's role in regulating IGF-II responses, especially in cancer.
Insulin-like growth factor II (IGF-II) is produced locally by many tissues of the body during periods of rapid cell division and remodeling. IGF-II is thought to play an important local role in regulation of cell growth and differentiation by binding to and activating the signaling mechanism of the IGF-I receptor. IGF-II is often expressed at high levels in tumor cells, and it has been shown that IGF-II provides an important stimulus for growth of some human cancers. The primary transmembrane binding protein for IGF-II also is capable of binding mannose 6-phosphorylated (Man-6-P) glycoproteins, hence, its name, the IGF-II/Man-6-P receptor. Because of the IGF-II/Man-6-P receptor's lack of signaling function and its active role in the internalization and subsequent degradation of its bound cargo, the IGF-II/Man-6-P receptor is thought to down-regulate IGF-II signaling by sequestering the growth factor and targeting it for destruction within the cell. It is also proposed that the receptor contributes to suppression of cell growth by binding Man-6-P ligands such as transforming growth factor-beta and lysosomal enzymes. In many human cancers, especially those of the liver, colon and breast, the M6P/IGFIIr gene shows a change called loss of heterozygosity (LOH), which causes reduced receptor synthesis and is the hallmark of a tumor suppressor.
Past Work by Our Laboratory:
The hypothesis governing work being done in our laboratory is that the main function of the IGF-II/Man-6-P receptor's IGF-II binding site is suppression of IGF-II-driven growth signals. Our earlier work, using both protein biochemical and molecular approaches, has allowed us to map the primary IGF-II binding domain to repeat eleven in the receptor's extracytoplasmic region. A nearby domain that enhances affinity of the receptor for IGF-II, and thereby cooperates with the primary binding site was also discovered by our laboratory. More recently, we have published new evidence that the IGF-II/Man-6-P receptor is a dimer and that interaction between two receptor half-molecules is necessary for high affinity binding of Man-6-P ligands at two sites on the receptor. This finding has important implications for cancer biology in that the receptor may be susceptible to inhibition in a dominant-negative manner, i.e., if one allele encoding the protein in a particular cell is mutant, it could bind to and interfere with functions of the non-mutant protein. We have also established that binding of a novel IGF-II/Man-6-P receptor ligand, uPAR, does not appear to be a physiologically important phenomenon.
Our Current Projects:
Ongoing projects in the laboratory are investigating:
- The nature of the dimer interaction in the high-affinity binding of Man-6-P ligands to the IGF-II/Man-6-P receptor.
- The effects of specific mutations of the ligand-binding regions on the ability of the IGF-II/Man6-P receptor to inhibit growth of cells and tumor development.
- The role of the IGF-II/Man-6-P receptor in the growth of prostate cancer cells.
- New proteomic approaches toward identifying novel ligands for the IGF-II/Man-6-P receptor.
The long-range goals of this research are to determine whether the tumor suppressor function of the IGF-II/Man-6-P receptor arises from its ability to bind IGF-II or Man-6-P ligands, and to exploit this information in devising new treatments for IGF-II-dependent cancers.
Kreiling, JL, Byrd, JC, and MacDonald, RG. (2005) Domain interactions of the insulin-like growth factor II/mannose 6-phosphate receptor. J. Biol. Chem. 280:21067-21077.
Allen-Gipson DS, Wyatt TA, Heires Aj, Sanderson SD, MacDonald RG, Floreani AA. (2005) Cigarette smoke extract increases C51 receptor expression in human bronchial epithelial cells. J Pharmacol Exp Ther. 314:476-482.
Veeramani S, Yuan T-C, Chen S-J, Lin F-F, MacDonald RG, Lin M-F. (2005) Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer. Endocrine-Related Cancer. 12:805-822.
Charette BD, MacDonald RG, Wetzel S, Berkowitz DB, Waldmann H. (2006) Protein structure similarity clustering: Dynamic treatment of PDB structures facilitates clustering. Angew Chem Int Ed Engl. 45:7766-7770. Abstract
Hawkes C, Jhamandas JH, Harris KH, Fu W, MacDonald RG, Kar S. (2006) Single transmembrane domain insulin-like growth factor-II/mannose-6-phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway. J Neurosci. 26:585-596. Abstract
Hawkes C, Amritraj A, MacDonald RG, Jhamandas JH, Kar S. (2007) Heterotrimeric G proteins and the single transmembrane domain IGF-II/M6P receptor: functional interaction and relevance to signaling. Mol Neurobiol. 35:329-345. Abstract
Fei X, Connelly CM, MacDonald RG, Berkowitz DB. (2008) A set of phosphatase-inert "molecule rulers" to probe for bivalent mannose 6-phosphate ligand-receptor interactions. Bioorg Med Chem Lett. 18(10):3085-9. Abstract
Hartman MA, Kreiling JL, Byrd JC, MacDonald RG. (2009) High-affinity ligand binding by wild type/mutant heteromeric complexes of the dimeric mannose 6-phosphate/insulin-like growth factor II receptor. FEBS J. 276(7):1915-29. Abstract
MacDonald R.G. and Chaney, W.G. USMLE Road Map Biochemistry. McGraw-Hill, New York, 2007.
Current Grants and Contracts:
P20 RR18759 (Johnson)
"Nebraska Center for Cellular Signaling"
09/19/03 - 06/30/13