Autocrine Extracellular Signal-regulated Kinase Activation in Normal Human Keratinocytes is not Interrupted by Calcium Triggering and is Involved in the Control of Cell Cycle at the Early Stage of Calcium-induced Differentiation

Abstract

Normal human epidermal keratinocytes (NHEK) respond to the autocrine activated extracellular signal-regulated kinase (ERK) signaling pathway, which contributes to the survival of keratinocytes. However, during the condition of calcium-induced differentiation, how the autocrine ERK signaling is regulated and affected is poorly understood. The purpose of this study was to understand and to obtain clues to the possible function of the autocrine ERK activation during the calcium-induced differentiation of NHEK. We demonstrated that the autocrine activated ERK was not interrupted by calcium triggering and that it was sustained for at least one day after changing the medium. We also found that the autocrine ERK activation was associated with the expression of cyclin D1 and the cell cycle regulation at the early stage of calcium triggering by treating the cells with the mitogen-activated protein kinase inhibitor PD98059. However, the PD98059 treatment did not have a significant influence on the expression of involucrin and loricrin. In addition, we demonstrated that autocrine ERK activation was associated with protein kinase C and p38MAPK signaling. We suggest that the activation of autocrine ERK is not interrupted by calcium triggering and it might participate in cell growth during the early stage of calcium-induced differentiation in NHEK.

Effects of Human Mesenchymal Stem Cells Coculture on Calcium-Induced Differentiation of Normal Human Keratinocytes

“…The MAPK pathways have been linked to keratinocyte cell survival and re‐epithelialization of skin . Previous study has suggested that Ca 2+ ‐induced activation of MAPK is important for survival of keratinocytes in early stage despite the induction of differentiation . Our data showed that Ca 2+ induced the activation of ERK, and p38 in NHEKs, which was suppressed by coculture with MSCs.…”

“…Activation of MAPK pathways is critical for keratinocyte survival even during the differentiation. It is demonstrated that autocrine‐activated ERK is not interrupted by Ca 2+ triggering in keratinocytes and sustained for at least early stage of differentiation program . Our data showed that both ERK and p38 were activated in NHEKs during the Ca 2+ treatment, but significantly decreased upon coculture with MSCs.…”

Calcium-Inducible MAPK/AP-1 Signaling Drives Semaphorin 3A Expression in Normal Human Epidermal Keratinocytes

“…Human epidermal keratinocytes maintain high ERK1/2 activity levels through the autocrine production of epidermal growth factor receptor ligands (Pastore et al, 2008). The transient inactivation of ERK1/2 suggests that a medium change induces a temporary lack of epidermal growth factor receptor ligands in the medium (Park et al, 2007). 2020) recently examined skin hyperesthesia in patients with chronic pruritus, such as AD, and showed that this was not related to hyperinnervation in the epidermis, as demonstrated by a decreased number of cutaneous nerves crossing the basement membrane; however, they did not report the Sema3A levels.…”

Immunohistochemical Studies of Cytokeratins and Differentiation Markers in Bovine Ocular Squamous Cell Carcinoma

“…Involucrin and filaggrin are considered markers of keratinocyte terminal differentiation. Synthesis of involucrin starts in stratum spinosum keratinocytes, after they have stopped their division, and is considered an early marker of terminal differentiation [ 14 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Involucrin expression could distinguish benign lesions from SCC [ 24 , 25 ].…”