Competing molecular interactions of aPKC isoforms regulate neuronal polarity

Abstract

Atypical protein kinase C (aPKC) isoforms ζ and λ interact with polarity complex protein Par3 and are evolutionarily conserved regulators of cell polarity. Prkcz encodes aPKC-ζ and PKM-ζ, a truncated, neuron-specific alternative transcript, and Prkcl encodes aPKC-λ. Here we show that, in embryonic hippocampal neurons, two aPKC isoforms, aPKC-λ and PKM-ζ, are expressed. The localization of these isoforms is spatially distinct in a polarized neuron. aPKC-λ, as well as Par3, localizes at the presumptive axon, whereas PKM-ζ and Par3 are distributed at non-axon-forming neurites. PKM-ζ competes with aPKC-λ for binding to Par3 and disrupts the aPKC-λ-Par3 complex. Silencing of PKM-ζ or overexpression of aPKC-λ in hippocampal neurons alters neuronal polarity, resulting in neurons with supernumerary axons. In contrast, the overexpression of PKM-ζ prevents axon specification. Our studies suggest a molecular model wherein mutually antagonistic intermolecular competition between aPKC isoforms directs the establishment of neuronal polarity.axonogenesis | symmetry breaking | neurodevelopment

Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma

“…For example, aPKCζ has been reported to be both increased and decreased in abundance in cancer, including glioblastoma (55, 56). aPKCΙ, and not aPKCζ, is the aPKC detected in most brain regions, except for cerebellum (57). Our analyses revealed that most glioblastoma tumor cell lines, as well as patient-derived xenografts, express more PRKCI than PRKCZ (fig.…”

CTCFdeletion syndrome: clinical features and epigenetic delineation

“…Prkcl encodes aPKC-λ, and Prkcz codes for aPKC-ζ and the alternatively transcribed PKM-ζ. Parker et al 27 reported that the localisation of these isoforms is spatially distinct in a polarised embryonic hippocampal neuron. Furthermore disruption of aPKC isoforms expression pattern alters neuron polarity and axon specification, suggesting that mutually antagonistic intermolecular competition between aPKC isoforms directs the establishment of neuronal polarity 26.…”

Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity

“…Finally, equal numbers of hypothalamic POMC neurons were present in adult POMC-λKO and WT mice (Fig. 3 F ), confirming that deletion of Pkc-λ during embryogenesis (earliest activity of the Pomc promoter) did not affect general POMC neuron development or cellular survival in adulthood (an important consideration given the role of aPKC in establishing neuronal polarity [25]).…”

“…Similarly, overexpression of PKC-λ or deletion of the truncated constitutively active PKC-ζ isoform PKM-ζ disrupts hippocampal neurogenesis (25). In this study, however, deletion of PKC-λ did not affect the number or localization of POMC neurons within the hypothalamus.…”

“…Little is known about the role of aPKC in the central nervous system (CNS), although both isoforms are expressed in many brain regions, including the hypothalamus (23), and aPKC is involved in establishing neuronal polarity during development (24,25). Involvement of CNS aPKC in metabolic regulation has been demonstrated for endotoxin-induced inflammatory anorexia but not acute pharmacological leptin-mediated anorexia (26).…”