PTPζ cleavage. The PTPζ-A and –B isoforms are cleaved in a similar manner. For simplicity’s sake, cleavage of PTPζ-B is shown. The ECD of PTPζ-B consists of a CA domain, an FNIII repeat, and a unique spacer region. S1 cleavage by either MMP-9 or ADAM-17 at the plasma membrane (PM), yields an 180kDa shed Z_B-ECD [30]. S2 cleavage by γ-secretase yields the 73kDa Z_B-ICD, which is found both in the cytosol and nucleus [30]. Molecular diagnostics, indicated by the magenta stars, could be developed to bind to the contactin1-binding site in the CA domain [78], the NgCAM, NCAM, NrCAM binding site in between the CA and FNIII repeat [20], the tenascin binding site in the FNIII repeat [70], or the pleiotrophin binding site in the spacer region [24].

LAR cleavage. The type I transmembrane protein LAR RPTP is composed of 3 Ig domains and 8 FNIII repeats in its ECD and two tandem tyrosine phosphatase domains in its ICD. It is cleaved by a furin-like endoprotease in the Golgi to yield a 150kDa E-subunit and an 85kDa P-subunit that remain non-covalently attached (S1) [36, 37]. In response to phorbol esters, high cell density, or calcium ionophores, a 150kDa segment of the LAR ECD is cleaved at the plasma membrane (PM) and shed by ADAM-17/TACE (S2) [40]. The γ-secretase complex then cleaves the transmembrane domain of LAR to yield a 70kDa membrane-free fragment, LAR-ICD, which is capable of translocating to the nucleus (S3) [31]. Molecular diagnostics like the ones used to identify extracellular PTPμ fragments in GBM tissue could be designed to bind to the heterophilic [4, 6] and homophilic [9] binding sites on LAR, as indicated by the magenta stars.