title: Thrombin enhances NGF-mediated neurite extension via increased and sustained activation of p44/42 MAPK and p38 MAPK.
abstract: Rapid neurite remodeling is fundamental to nervous system development and plasticity. It involves neurite extension that is regulated by NGF through PI3K/AKT, p44/42 MAPK and p38 MAPK. It also involves neurite retraction that is regulated by the serine protease, thrombin. However, the intracellular signaling pathway by which thrombin causes neurite retraction is unknown. Using the PC12 neuronal cell model, we demonstrate that thrombin utilizes the PI3K/AKT pathway for neurite retraction in NGF-differentiated cells. Interestingly, however, we found that thrombin enhances NGF-induced neurite extension in differentiating cells. This is achieved through increased and sustained activation of p44/42 MAPK and p38 MAPK. Thus, thrombin elicits opposing effects in differentiated and differentiating cells through activation of distinct signaling pathways: neurite retraction in differentiated cells via PI3K/AKT, and neurite extension in differentiating cells via p44/42 MAPK and p38 MAPK. These findings, which also point to a novel cooperative role between thrombin and NGF, have significant implications in the development of the nervous system and the disease processes that afflicts it as well as in the potential of combined thrombin and NGF therapy for impaired learning and memory, and spinal cord injury which all require neurite extension and remodeling.
authors: Departments of Cell Biology and Anatomy, Southern Alberta Cancer Research and Hotchkiss Brain Institutes, University of Calgary, Calgary, Alberta, Canada.
authors: Rania E
authors: RE
authors: Mufti
authors: Departments of Cell Biology and Anatomy, Southern Alberta Cancer Research and Hotchkiss Brain Institutes, University of Calgary, Calgary, Alberta, Canada.
authors: Krishna
authors: K
authors: Sarker
authors: Laboratory of Medical Genetics, Harbin Medical University, Harbin, China.
authors: Yan
authors: Y
authors: Jin
authors: Laboratory of Medical Genetics, Harbin Medical University, Harbin, China.
authors: Songbin
authors: S
authors: Fu
authors: Departments of Cell Biology and Anatomy, Southern Alberta Cancer Research and Hotchkiss Brain Institutes, University of Calgary, Calgary, Alberta, Canada; Biochemistry and Molecular Biology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors: Jesusa L
authors: JL
authors: Rosales
authors: Departments of Cell Biology and Anatomy, Southern Alberta Cancer Research and Hotchkiss Brain Institutes, University of Calgary, Calgary, Alberta, Canada.
authors: Ki-Young
authors: KY
authors: Lee
mesh_terms: D000818:Animals; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis; D016716:PC12 Cells; D051381:Rats; D013917:Thrombin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020932:Nerve Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin