Interplay of Specific Trans- and Juxtamembrane Interfaces in Plexin A3 Dimerization and Signal Transduction

Abstract

Plexins are transmembrane proteins that serve as guidance receptors during angiogenesis, lymphangiogenesis, neuronal development, and zebrafish fin regeneration, with a putative role in cancer metastasis. Receptor dimerization or clustering, induced by extracellular ligand binding but modulated in part by the plexin transmembrane (TM) and juxtamembrane (JM) domains, is thought to drive plexin activity. Previous studies indicate that isolated plexin TM domains interact through a conserved, small-x3-small packing motif, and the cytosolic JM region interacts through a hydrophobic heptad repeat; however, the roles and interplay of these regions in plexin signal transduction remain unclear. Using an integrated experimental and simulation approach, we find disruption of the small-x3-small motifs in the Danio rerio Plexin A3 TM domain enhances dimerization of the TM-JM domain by enhancing JM-mediated dimerization. Furthermore, mutations of the cytosolic JM heptad repeat that disrupt dimerization do so even in the presence of TM domain mutations. However, mutations to the small-x3-small TM interfaces also disrupt Plexin A3 signaling in a zebrafish axonal guidance assay, indicating the importance of this TM interface in signal transduction. Collectively, our experimental and simulation results demonstrate that multiple TM and JM interfaces exist in the Plexin A3 homodimer, and these interfaces independently regulate dimerization that is important in Plexin A3 signal transduction.

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

“…We were able to identify genes coding for cell surface-bound proteins, which can potentially be explored as targets for radiolabeled monoclonal antibodies for positron emission tomography (PET)-based detection of metastatic prostate cancer. These markers include ADAM15 [48], CD276 [49], NRP1 [52,53], SCARB1 [54], and PLXNA3 [56], all of which have been reported to be overexpressed in metastatic PrCa. Elevated expression of genes such as ABCC5 [50], LRFN1 [59], ELOVL6 [58], and HTR2B [61] have been associated with metastasis in other cancer types.…”

“…ADAM15 (ADAM metallopeptidase domain 15) codes for a protein that interacts with vascular endothelium and factors during prostate cancer metastasis [48], while the overexpression of CD276 (or B7H3) proved to be a driving factor in cancer migration and invasion [49]. The other surface protein genes listed in Table 1 include: ABCC5 (ATP binding cassette subfamily C member 5) [50], CD36 (CD36 molecule) [51], NRP1 (neuropilin 1) [52,53], SCARB1 (scavenger receptor class B member 1) [54], TMEM132A (transmembrane protein 132A) [55], PLXNA3 (plexin A3) [56], SERPINI1 (serpin family I member 1) [57], ELOVL6 (ELOVL fatty acid elongase 6) [58], LRFN1 (leucine-rich repeat and fibronectin type III domain containing 1) [59], THY1 (Thy-1 cell surface antigen) [60], and HTR2B (5-hydroxytryptamine receptor 2B) [61]. The expression levels of NRP1 [52,53] and SCARB1 [54] were reported to be upregulated in metastatic mCRPCs.…”

“…The expression levels of NRP1 [52,53] and SCARB1 [54] were reported to be upregulated in metastatic mCRPCs. PLXNA3, a member of the plexin family of genes coding for a receptor protein, is involved in the guidance of vascular and lymphatic vessels during metastasis [56]. The rest of the genes above were also over-expressed metastatic cancers originating from breast cancer (ABCC5), kidney renal clear carcinoma (LRFN1), hepatocellular carcinoma (ELOVL6), and uveal melanoma (HTR2B).…”