ERK and P13K
ERK and P13K
ERK is involved in neural processes as varied as the genesis of neural progenitors, learning, and memory. In the developing brain, the ERKs respond mostly to growth factors in the activation of receptor tyrosine kinases such as MET. In the mature nervous system, ERKs are activated in response to synaptic activity. ERK1 is 84% identical to ERK2 in sequence. Not much is known their unique actions because both are expressed at the same time, have the same substrate specificity, and are coordinately activated. ERKs are most highly expressed in neurons, though the relative expression of ERK2 is greater than ERK1. KO of ERK1 results in no overt phenotype in mice while KO of ERK2 is lethal to the early embryo.2
A body of studies on certain disorders with high penetrance of ASD converge on the ERK and Pl3K intracellular signaling pathways. ERK and Pl3K indirectly influences the mRNA translation to influence developmental functions, such as the cell cycle, cell survival, differentiation, and motility. Receptor tyrosine kinases (RTKs) can transduce signals through either of these intracellular kinase pathways. The connection between ERK/Pl3K signaling disruption and ASD are evident in tuberous sclerosis and neurofibromatosis type 1, where enhanced mTOR downstream activity is due to different elements of the ERK/Pl3K pathway are disrupted genetically. Also, ERK and Pl3K are dependent on normal cholesterol biosynthesis, which is absent in Smith-Lemli-Opitz syndrome. Other elements of the Pl3K signaling pathways such as phosphatase and tensin homolog (PTEN) are correlated with high prevalence of ASD. Another link includes the disruption of X-linked MECP2, which binds to specific regions of certain genes that control gene transcription. MECP2 binding directly regulates transcription of key genes involved in MET RTK signaling pathway, which is implicated in ASD risk. These genes include encoding for Met in the ERK/Pl3K downstream signaling pathways.
It has been demonstrated that mTOR activation can reverse behavioral and structural pathology in mice with Pten, tuberous 1, and neurofibromin 1 mutations in mice with no reported side effects. It is thought that different genetic routes to alter RTK function by modulating the ERK/Pl3K signaling pathways, combine with environmental factors that also modulate these signaling pathways to drive the neurodevelopment system over the threshold for disorder expression.
Given that ERK/Pl3K signaling is widely distributed throughout multiple organ systems, it is unknown where disorder specificity arises. One hypothesis suggests that risk for more global neurodevelopmental disruptions increases when the genetic “hits” are downstream from the molecular components that are involved in initial RTK activation, which are the growth factors or receptors themselves. Consistent with this hypothesis arises from mutations in NF1, AKT, TSC1, and TSC2 typically result in widespread severe clinical problems. Alternatively, the corollary to this hypothesis would be that mutations in upstream genes encoding RTKs or proteins that regulate growth factor availability would place signaling through this pathway at risk, but require additional genetic or environmental triggers to cause neurodevelopmental disruption, which is consistent with the identification of neuregulin 1. Although both ERBB4 and MET activate Pl3K signaling, the different timing and patterns of expression of each of these RTKs in developing cerebral cortex may account for the distinct neurodevelopmental disruptions characteristic of each disorder. 1
1. Levitt, P. et. al. The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J Clin Invest. 2009 Apr;119(4):747-54.
2. Samuels, IS et. al. MAP'ing CNS development and cognition: an ERKsome process.Neuron. 2009 Jan 29;61(2):160-7. PMID 19186160