Soluble M6P/IGF2R Released by TACE Controls Angiogenesis via Blocking Plasminogen Activation

Abstract

Rationale:The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R).Objective: Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system. Methods and Results:

Dissecting Mannose 6-Phosphate-Insulin-like Growth Factor 2 Receptor Complexes That Control Activation and Uptake of Plasminogen in Cells

“…We will test this possibility in future studies. Taken together, direct interactions of M6P-IGF2R with uPAR and with Plg, as shown by us elsewhere (18,21,41) and in the present study, might provide a control to restrict plasmin activity to specific time and sites and thus to prevent unfavorable degradation of the surrounding structures during cell migration. Furthermore, these interactions might be important for the processing of specific substrates, such as latent transforming growth factor ␤ (17, 19) or uPAR itself (21).…”

“…7). This finding provides another strong indication for involvement of M6P-IGF2R in Plg uptake and also widens our view on the pharmacological potential of pep18 -36 because its inhibitory effect on neovascularization and tumor growth is obviously not restricted to a blockade of binding of Plg to uPA as originally described by us (41). We hypothesize that the binding of Plg via this particular region changes the conformation of Plg so that the latter binds subsequently to further sites encompassed either within M6P-IGF2R itself or other Plg binding receptors, which ultimately amplifies its internalization.…”

“…The expression of M6P-IGF2R both facilitates the proteolytic cleavage of uPAR, thus leading to the loss of uPA binding and subsequently to the blunted Plg activation and cell migration (21), and down-regulates ␣V␤3 integrin expression (21). Furthermore, we have demonstrated that soluble M6P-IGF2R also dampens Plg activation on the cell surface (41). Here, we complement these data by showing that M6P-IGF2R mediates Plg internalization.…”

“…Previously we showed that pep18 -36 blocked binding of Plg to uPA and inhibited Plg activation (41). Surprisingly, pep18 -36 enhanced Plg internalization by about 114% in control-and 85% in M6P-IGF2R-silenced cells.…”

Insulin-Like Growth Factor-II/Cation-Independent Mannose 6-Phosphate Receptor in Neurodegenerative Diseases

“…A truncated form of the receptor representing a proteolytic cleavage product of the receptor’s ectodomain has been identified in serum and other physiological fluids of a variety of mammalian species [27, 28]. The significance of the truncated receptor form in relation to the functioning of the IGF-II/M6P receptor under in vivo conditions remains unclear; however, it appears that proteolytic cleavage at the cell surface to release the receptor’s ectodomain may be one means to degrade and thus down-regulate levels of the IGF-II/M6P receptor [29, 30]. …”