Fig 8

Proposed mechanisms underlying the differential activations and oncogenic activities of Matriptase-1 in hai1a and atp1b1a mutants to induce cell proliferation, EMT and invasiveness.

(A) Model of Matriptase activity restriction in the wild-type zebrafish epidermis. Hai1a is tightly associated with Matriptase, thereby inhibiting its activity, both in peridermal and basal cells. In addition, Matriptase trans-layer signaling from the periderm to the basal layer is restrained by confined levels of Matriptase at the basal side of peridermal cells. (B) Upon loss of Hai1a, Matriptase 1 is no longer inhibited (red star), leading to the cleavage of adjacent Par2b (orange asterisk), which in turn activates the EGFR-PLD pathway, to induce hyperproliferation and expression of mmp9 (a marker for EMT). Mild hypotonicity (small blue star), most likely due to compromised epidermal integrity, further enhances Matriptase activity levels. Note that additional pathways downstream of Par2b have been described, which lead to additional pre-neoplastic events, like sterile inflammation; however, they do not include PI3K [23]. (C) More extreme hypotonicity in the pericellular space (due to loss of ATP1b1a or Pax2a; large blue star) causes (moderate) Matriptase activation even in the presence of Hai1a. This, however, only has subtle effects on epidermal cells (Fig 7K,7L), unless occurring in conjunction with the loss of epithelial polarity (due to loss of ATP1b1a or Lgl2), allowing Matriptase to shift towards the basal side of peridermal cells, thereby getting into physical contact and to cleave / activate Par2b and other, not yet identified targets (indicated by?) on underlying basal keratinocytes in trans. These targets activate a PI3K-pAKT-mTORC1-NFkB pathway in basal cells resulting in pre-neoplastic events like hyperproliferation, EMT and, in contrast to hai1a mutants, strong invasiveness of basal cells.