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Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes Its Activity in Cancer Cells

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Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes Its Activity in Cancer Cells bioRxiv preprint doi: https://doi.org/10.1101/672147; this version posted October 7, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells Elizabeth Bloch1¶ , Eden L. Sikorski1¶, David Pontoriero2, Evan K. Day2, Bryan W. Berger2, Matthew J. Lazzara2, and Damien Thévenin1* 1Department of Chemistry, Lehigh University, Bethlehem, PA 18015; 2Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22903 *To whom correspondence should be addressed: [email protected]; Tel. (610) 758-2886 ¶These authors contributed equally to this work Despite the critical regulatory roles that receptor Introduction protein tyrosine phosphatases (RPTP) play in mammalian signal transduction, the detailed Normally, cell signaling by receptor tyrosine kinases structural basis for the regulation of their catalytic (RTKs) is tightly controlled by the counterbalancing activity is not fully understood, nor are they actions of protein tyrosine phosphatases (PTPs), generally therapeutically targetable. It is due, in which dephosphorylate regulatory tyrosines on RTKs part, to the lack of known natural ligands or to attenuate their signal-initiating potency. Twenty- selective agonists. In contrast to conventional two PTPs are classified as receptor-like PTPs structure-function relationship for receptor (RPTPs), which all share the same architecture: an tyrosine kinases (RTKs), the activity of RPTPs has extracellular region (often including fibronectin type been reported to be suppressed by dimerization, III repeats and immunoglobin-like domains), a single- which may prevent their access to their RTK pass transmembrane segment, and either one or two substrates. We report here that: (i) cytosolic highly conserved PTP domains (1, 2). These homodimerization of PTPRJ (also known as DEP- integral membrane PTPs are some of the most 1) is regulated by specific transmembrane (TM) important regulators of RTKs, and their normal residues, and (ii) disrupting these interactions can function is critical for homeostatic control (2, 3). destabilize full-length PTPRJ homodimerization Interestingly, while RPTPs can act as suppressors of in cells, reduce the phosphorylation of EGFR (a several tumors, including colon, lung, breast, and known substrate) and downstream signaling thyroid cancers, they can also act as oncogenes when effectors, antagonize EGFR-driven cell deregulated either through reduced expression, often phenotypes, and promote substrate access. We due to loss of heterozygosity or loss-of-function demonstrate these points in human cancer cells mutations (4-8). Notably, fewer than one-third of using both mutational studies and through the reported point mutations occur within the identification of a peptide designed to bind to the intracellular phosphatase domains indicating PTPRJ TM domain. This peptide is the first inactivation occurs without structural changes to the example of such allosteric agonist of RPTPs. This catalytic domain (9). RPTPs have therefore long been study, therefore, provides not only fundamental viewed as potential therapeutic targets. structure-function insights on how PTPRJ activity Of the RPTPs characterized, PTPRJ (also known as is tuned by TM interactions in cells but also DEP-1) is particularly intriguing as it has been opportunities to develop a unique class of agents identified as a regulator of C-terminal tyrosine that could be used as tools to probe RPTPs phosphorylation in the epidermal growth factor signaling regulating mechanisms or for receptor (EGFR) (10-12), a frequent driver of therapeutic purposes in cancers driven by RTK oncogenic signaling across numerous cancers. signaling. Deregulation of mechanisms controlling EGFR 1 bioRxiv preprint doi: https://doi.org/10.1101/672147; this version posted October 7, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. activation and expression results in abnormal cell to identify and characterize a synthetic peptide that growth and proliferation. PTPRJ has a direct role in interacts with and disrupts PTPRJ homodimers regulating EGFR activity, implicating it as a relevant through specific TM interactions. We show the tumor suppressor. Furthermore, PTPRJ is often delivery of this peptide selectively modulates the down-regulated in numerous cancers, and its dimerization state and activity of PTPRJ in EGFR- restoration was shown to inhibit malignant driven cancer cells. The present study represents a phenotypes both in vitro and in vivo (13). structure-function determination of the TM domain of PTPRJ, and a new way to selectively modulate the While small molecule allosteric inhibition of some activity of this important class of phosphatases in non-receptor PTPs is now possible (14), methods to cancer cells. specifically target RPTPs are missing, due, in part, to the limited understanding of their mechanism of action and the lack of known natural ligands. Indeed, Results compared to the structure-function relationships for RTKs, relatively little has been elucidated for RPTPs. PTPRJ self-association is mediated by For instance, the reported ability of specific TM residues homodimerization to antagonize RPTP catalytic activity appears to be a general feature of the entire To assess whether the transmembrane (TM) domain family, but there is no proposed common model. The and specific amino acid residues play a role in the “head-to-toe” dimerization model for the PTP D1 and self-association of PTPRJ, we first used the D2 intracellular domains, proposed originally by Barr dominant-negative AraC-based transcriptional et al. for PTPRG, is generally accepted for RPTPs reporter assay (DN-AraTM) (21, 22). This assay with tandemly repeated intracellular domains (1). reports on the propensity of TM domains to self- However, since PTPRJ and other members of the R3 associate and heterodimerize in cell membranes. sub-family have only one catalytic intracellular PTP Briefly, it relies on a protein chimera containing the domain, the “head-to-toe” model and the “inhibitory receptor domain of interest fused to either the wedge” model proposed for PTPRA (15, 16) seem to transcription factor AraC (which is active at the be incompatible. Nevertheless, the reported ability of araBAD promoter as a homodimer), or to an AraC homodimerization to antagonize PTPRJ catalytic mutant unable to activate transcription (AraC*). Both activity and substrate access presents potential chimeras include an N-terminal maltose-binding opportunities to develop strategies to promote RPTP protein (MBP) fusion that directs chimera insertion in activity against their oncogenic RTK substrate (17). the inner membrane of AraC-deficient E. coli While the transmembrane (TM) domain of several (SB1676). Homodimerization of AraC (a result from RPTPs has been proposed to be involved in their receptor domain self-association) induces the homodimerization (17-20), and therefore represents transcription of the gene coding for the green an attractive target, there is no clear structure-based fluorescent protein (GFP). Thus, GFP fluorescence proposal for how this occurs. Therefore, elucidating intensity is a measure of receptor domain the contribution of the TM domain in RPTPs, and dimerization. particularly in PTPRJ regulation, can provide When the TM domain of wild-type PTPRJ (WT) significant insight into how these receptors function, (Figure 1A) was expressed as a fusion to AraC, a interact, and eventually be modulated, leading to new strong GFP signal was observed, indicating that the methods to target signaling of oncogenic RTKs that TM domain has a high propensity to self-associate may be less susceptible to common mechanisms of (Figure 1B; black bar). On the other hand, when resistance. PTPRJ WT-AraC* was co-expressed as a competitor Here, we employed mutational studies to show that to PTPRJ WT-AraC, a significant decrease in GFP PTPRJ homodimerization is regulated through signal was observed (Figure 1B, hashed bar), specific TM residue interactions. Furthermore, consistent with specific TM-TM interactions. Having disrupting these interactions antagonizes PTPRJ confirmed that PTPRJ self-associates, in part through homodimerization, thereby promoting its the TM domain, we sought to identify the amino acids phosphatase activity and ultimately inhibiting EGFR- required for this interaction. To alter interfacial driven cell phenotypes. We used these new findings packing and introduce steric clashes, amino acids in 2 bioRxiv preprint doi: https://doi.org/10.1101/672147; this version posted October 7, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. the TM region with small side chains (Ala, Cys, Gly,) does expression of WT PTPRJ significantly inhibit were mutated to leucine, while those with larger side EGFR-driven cell migration when compared to chains (Ile, Leu, Phe, Val) were mutated to alanine empty
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