A C-terminal fragment of parathyroid hormone-related protein, PTH-rP(107-111) stimulates membrane-associated protein kinases C's activity and modulates the proliferation of human and murine skin keratinocytes

Low concentrations of the C-terminal parathyroid hormone-related protein (PTHrP) fragments, PTHrP-(107-111) and PTHrP-(107-139), stimulated membrane-associated protein kinase Cs (PKCs), but not adenylyl cyclase or an internal Ca2+ surge, in early passage human skin keratinocytes and BALB/MK-2 murine skin keratinocytes. The fragment maximally stimulated membrane-associated PKCs in BALB/MK-2 cells at 5 x 10(-9) to 10(-8) M. The maximally PKC-stimulating concentrations of PTHrP-(107-111) also stopped or stimulated BALB/MK-2 keratinocyte proliferation depending on whether the cells were, respectively, cycling or quiescent at the time of exposure. Thus, just one brief (30-minute) pulse of 10(-8) M PTHrP-(107-111) stopped the proliferation of BALB/MK-2 keratinocytes for at least 5 days. On the other hand, daily 30-minute pulses of 10(-8) M PTHrP-(107-111) started and then maintained the proliferation of initially quiescent BALB/MK-2 cells. Similarly PTHrP-(107-111) inhibited DNA synthesis by cycling primary adult human keratinocytes, but it stimulated DNA synthesis by quiescent human keratinocytes.