AKAP11, or A-kinase anchoring protein 11, is a protein found in the human body, encoded by the AKAP11 gene on chromosome 13, at band 13q14.11. As a member of the A-kinase anchor protein family, AKAP11 contributes to the complex network of proteins that regulate cellular activities.
Understanding AKAP11’s Cellular Role
AKAP11 functions primarily by binding to the regulatory subunit of protein kinase A (PKA), an enzyme with a broad impact on cellular processes. This binding action confines PKA to specific locations within the cell, a mechanism known as compartmentalization. By anchoring PKA, AKAP11 ensures that cellular signals are precise and targeted, preventing widespread and unregulated PKA activity.
This anchoring is important for various cellular processes, including intracellular signal transduction and the regulation of PKA signaling. AKAP11 also interacts with protein phosphatase 1, an enzyme involved in cellular regulation. Studies indicate that AKAP11 may play a role in controlling the cell cycle in somatic and germ cells.
AKAP11 can also function as an autophagy receptor, mediating the selective degradation of PKA’s regulatory subunit RI. This degradation, induced by conditions like glucose starvation, leads to PKA activation. Activated PKA then enhances signaling pathways, such as the PKA-cAMP response element-binding (CREB) pathway, boosting mitochondrial respiration and ATP production, supporting cell survival during energy stress.
AKAP11’s Impact on Health
Dysregulation or mutations in AKAP11 have been linked to several health conditions, especially neurological disorders. Rare protein-truncating variants in the AKAP11 gene have been identified as a risk factor for both bipolar disorder and schizophrenia. These loss-of-function mutations in AKAP11 are considered the strongest genetic risk factor for bipolar disorder, increasing the risk several-fold.
The connection between AKAP11 and these psychiatric conditions suggests a shared underlying mechanism. Research indicates that the loss of AKAP11 function can disrupt PKA activity and impair cellular functions in neurons, pathways associated with psychiatric diseases. AKAP11 deficiency distorts the activity of PKA and glycogen synthase kinase 3 (GSK3) in neurons.
The protein product of AKAP11 interacts with GSK3B, a molecular pathway lithium, a common treatment for bipolar disorder, is thought to modify. This interaction suggests that understanding AKAP11’s role could offer insights into how lithium works and potentially lead to new treatments. AKAP11 is also implicated in neuropsychiatric, skeletal, and other physiological systems.
Emerging Research on AKAP11
Current research into AKAP11 is exploring its roles and potential as a therapeutic target. Scientists are using multi-omics approaches, cell biology, and electrophysiology analysis in mouse models and human induced neurons to understand AKAP11’s functions. These studies aim to delineate how AKAP11 couples PKA kinase network regulation to synaptic transmission, providing insights into mechanisms underlying psychiatric diseases.
AKAP11’s promotion of autophagic degradation of PKA regulatory subunits suggests a model where selective degradation increases free PKA catalytic subunits, promoting PKA signaling. This mechanism potentiates PKA-cAMP response element-binding transcription factor activity, boosting mitochondrial metabolism and conferring resistance to glucose deprivation, a process tumor cells may exploit. Suppressing AKAP11 levels in tumor cells inhibits tumor cell growth by blocking PKA activation, highlighting AKAP11-mediated autophagy as a novel therapeutic target for certain cancers.