Two Closely Related Human Members of Chitinase-like Family, CHI3L1 and CHI3L2, Activate ERK1/2 in 293 and U373 Cells but Have the Different Influence on Cell Proliferation

Abstract

The activation of extracellular signal-regulated kinases (ERK1/2) has been associated with specific outcomes. Sustained activation of ERK1/2 by nerve growth factor (NGF) is associated with translocation of ERKs to the nucleus of PC12 cells and precedes their differentiation into sympathetic-like neurons whereas transient activation by epidermal growth factor (EGF) leads to cell proliferation. It was demonstrated that different growth factors initiating the same cellular signaling pathways may lead to the different cell destiny, either to proliferation or to the inhibition of mitogenesis and apoptosis. Thus, further investigation on kinetic differences in activation of certain signal cascades in different cell types by biologically different agents are necessary for understanding the mechanisms as to how cells make a choice between proliferation and differentiation.It was reported that chitinase 3-like 1 (CHI3L1) protein promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts similarly to insulin-like growth factor 1 (IGF1). Both are involved in mediating the mitogenic response through the signal-regulated kinases ERK1/2. In addition, CHI3L1 which is highly expressed in different tumors including glioblastomas possesses oncogenic properties. As we found earlier, chitinase 3-like 2 (CHI3L2) most closely related to human CHI3L1 also showed increased expression in glial tumors at both the RNA and protein levels and stimulated the activation of the MAPK pathway through phosphorylation of ERK1/2 in 293 and U87 MG cells. The work described here demonstrates the influence of CHI3L2 and CHI3L1 on the duration of MAPK cellular signaling and phosphorylated ERK1/2 translocation to the nucleus. In contrast to the activation of ERK1/2 phosphorylation by CHI3L1 that leads to a proliferative signal (similar to the EGF effect in PC12 cells), activation of ERK1/2 phosphorylation by CHI3L2 (similar to NGF) inhibits cell mitogenesis and proliferation.

Role of Chitinase 3–Like-1 in Interleukin-18–Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung

“…To evaluate this speculation we focused on chitinase 3-like-1 (Chi3l1) (also called as YKL-40 in humans and BRP-39 in rodents), the prototypic CLP (1). These studies supported this speculation by demonstrating that Chi3l1 plays a major role in anti-pathogen, antigen-induced and oxidant-induced inflammatory, repair and remodeling responses by regulating a variety of essential biologic processes including oxidant injury, apoptosis, pyroptosis, inflammasome activation, Th1/Th2 inflammatory balance, M2 macrophage differentiation, TGF-β1 elaboration, dendritic cell accumulation and the activation of mitogen activated protein kinase (MAPK), Akt/protein kinase B and Wnt/β-catenin signaling (4)(5)(6)(7)(8)(9)(10).…”

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

“…To determine whether CHI3L1 is dysregulated in pale ear mice, we evaluated lung lysate Chi3l1 mRNA and bronchoalveolar lavage (BAL) CHI3L1 protein in WT and pale ear mice at baseline and after bleomycin challenge. These assessments were inflammation, repair, and remodeling responses by regulating a variety of essential biologic processes, including oxidant injury, apoptosis, pyroptosis, inflammasome activation, Th1/Th2 inflammatory balance, M2 macrophage differentiation, TGF-β1 elaboration, dendritic cell accumulation and activation, and MAPK and AKT signaling (18,(20)(21)(22)(23)(24)(25). The potential importance of CHI3L1-induced responses can also be seen in the large number of diseases characterized by inflammation and remodeling in which CHI3L1 excess has been documented (reviewed in refs.…”

Cancer Genes and Chromosome Instability

“…Addition of CHI3L1 to cell medium increased mitogenic and proliferative properties of 293 cells (human embryonic kidney 293 cells, also often referred to as HEK293) [25,26]. 293 cells stably transfected with CHI3L1 have an accelerated growth rate relatively to the parental cells and can undergo anchorageindependent growth in soft agar that is one of the consistent indicators of oncogenic transformation [25,27].…”