LKB1 and SAD Kinases Define a Pathway Required for the Polarization of Cortical Neurons

Abstract

The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. We show here that the serine/threonine kinase LKB1, previously implicated in the establishment of epithelial polarity and control of cell growth, is required for axon specification during neuronal polarization in the mammalian cerebral cortex. LKB1 polarizing activity requires its association with the pseudokinase Stradalpha and phosphorylation by kinases such as PKA and p90RSK, which transduce neurite outgrowth-promoting cues. Once activated, LKB1 phosphorylates and thereby activates SAD-A and SAD-B kinases, which are also required for neuronal polarization in the cerebral cortex. SAD kinases, in turn, phosphorylate effectors such as microtubule-associated proteins that implement polarization. Thus, we provide evidence in vivo and in vitro for a multikinase pathway that links extracellular signals to the intracellular machinery required for axon specification.

Phosphorylation of Serine 399 in LKB1 Protein Short Form by Protein Kinase Cζ Is Required for Its Nucleocytoplasmic Transport and Consequent AMP-activated Protein Kinase (AMPK) Activation

“…Moreover, LKB1 L and LKB1 S have comparable responses to ONOO Ϫ /metformin treatment, suggesting that Ser-399 in LKB1 S mimics the functionality of Ser-431/428 in LKB1 L . This rectifies previous, seemingly paradoxical findings (22,26,28,29,35,36) regarding the necessity of the Ser-431/428 site in LKB1 L by establishing that the Ser-399 site plays a compensatory role in LKB1 S .…”

“…This implies that alternative pathway(s) is (are) implicated in PKA-induced AMPK activation, which further supports the notion that regulation and activity of LKB1 are context-dependent (34). Other studies (35,36) have suggested an important regulatory role played by post-translational modifications in LKB1. It is probable that LKB1 is differentially phosphorylated by different stimuli in different cell types (25), warranting further investigation of the LKB1 regulatory C-terminal domain.…”

LKB1; linking cell structure and tumor suppression

“…LKB1 can also regulate the polarization of lung cancer cell lines in association with recruitment of the small GTPase, Cdc42, a known regulator of cell polarity see Etienne-Manneville, 2008). Conditional knockout and in vivo RNAi approaches have shown that Lkb1 controls axon specification in a manner that requires the AMPK-related SAD-A and SAD-B kinases (Barnes et al, 2007;Shelly et al, 2007). RNAi studies also showed that LKB1 is required for neuronal migration and centrosome positioning (Asada et al, 2007).…”

Mitochondrial biogenesis is required for axonal growth

“…It has recently been demonstrated that an increase in cAMP levels leads to activation of LKB1, which then activates AMPK. The role of cAMP in axon initiation during neuronal polarisation is to regulate the downstream kinase LKB1 by phosphorylation (Barnes et al, 2007;Shelly et al, 2007), which also co-activates mitochondrial biogenesis through AMPK. Furthermore, TAK1, which is activated by TGFβ signalling and controls axonal growth, co-activates mitochondrial biogenesis through AMPK (White et al, 2008;Xie et al, 2006;Yu et al, 2014).…”