Although it is accepted that glycans play important biological functions, the activation of receptor-type enzymes by glycans has not yet been in the list of the functions. It is emerging that the interactions of PTPσ, a member of type IIa receptor tyrosine phosphatases, with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We found that the extracellular CS induced in neural injuries monomerizes and activates PTPσ on axon terminals, where it dephosphorylates cortactin and disrupts autophagy flux. As a consequence, the CS-PTPσ axis induces dystrophic endballs in axon terminals and inhibits axon regeneration. In contrast, HS oligomerizes and inactivates PTPσ, and promotes axon regeneration. These opposite effects of CS and HS depend on the amounts of special sulfation patterns of these glycans in the brain, which preferentially bind to PTPσ1). The axon growth arrest may play not only pathologic but also physiologic roles, and thus the glycans-PTPσ axis may be important for the coordination of axon extension and synapse formation2,3). Indeed, the combination of PTPσ and HS serve as an important organizer of excitatory synapses. The counteraction of CS and HS through PTPσ prompted us to investigate another possibility: crosstalk between receptor-type tyrosine phosphatase and receptor-type tyrosine kinase. Indeed, it was reported that heparin binds to anaplastic lymphoma kinase (ALK). ALK is an orphan receptor with tyrosine kinase activity, and its mutations play a critical role in tumor development. We found that ALK is expressed in the central nervous system and promotes axon extension. Using the method proximity-dependent biotin identification, we determined that PTPσ and ALK have several common substrates including cortactin. Therefore, we speculate that the crosstalk of PTPσ and ALK through glycans may play a role in neural functions in physiological and pathological conditions.Finally, I would like to address another important issue. Individual studies such as those described above are crucial to the advancement of the life sciences. But, when considering life science as a whole, it is no exaggeration to say that the overwhelming lack of information on glycans, one of the three major life chains, compared to genomes and proteins, has limited our ability to solve life. In fact, while acknowledging the importance of the high contribution of glycans to life activities, most researchers have tried to understand life by avoiding glycans. The complexity and diversity of glycan structures has been the biggest bottleneck in this problem, but now the technological basis is in place to solve it. It is time for us to develop a research infrastructure that will boost glycan information to the level of genome and protein information and make the big data available to researchers in various fields, including glycoscience.References 1) Sakamoto K, Ozaki T, Ko YC, Tsai CF, Gong Y, Morozumi M, Ishikawa Y, Uchimura K, Nadanaka S, Kitagawa H, Zulueta MML, Bandaru A, Tamura JI, 2) Tran AP, Warren PM, Silver J. Regulation of autophagy by inhibitory CSPG interactions with receptor PTPσ and its impact on plasticity and 3) Sakamoto K, Ozaki T, Suzuki Y, Kadomatsu K. Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis. Int J Mol Sci. 2021 May Hung SC, Kadomatsu K. Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis. Nat Chem Biol. 2019 Jul;15(7):699-709.regeneration after spinal cord injury. Exp Neurol. 2020 Jun;328:113276. 24;22(11):552425Invited LectureKenji Kadomatsu
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