Human and mouse cells have similar exon/intron usage and spacing. AKAP12 has three independent promoters, α, β, and γ. The gamma promoter is active only in the testes while the α and β are co-active in most cells and tissues studied. Exons 1A1 and 1A2 combine to then splice to a common splice acceptor on Exon 2 used by Exon 1B. Exons 1A1 and 1A2 produce the N-terminal 103 amino acids of "AKAP12 alpha" whereas Exon 1B encodes the N-terminal 8 amino acids of "AKAP12 β"; the remaining amino acids are encoded in Exon 2. "AKAP12 gamma" is encoded by a read-through transcript starting in the intron upstream of Exon 2, utilizing an in-frame ATG in Exon 2. Therefore, the α, β, and γ transcripts encode proteins that only differ in their N-termini.

A: Except for testes, most cells express four major isoforms of AKAP12 protein. The 305 kDa isoforms is the myristylated AKAP12alpha whereas the 287 kDa isoforms is AKAP12beta. The 250 kDa and 43 kDa isoforms are proteolytic cleavage products common to the AKAP12alpha and beta isoforms.

B: Human AKAP12alpha encodes a 1,780 amino acids full-length protein. The first about 1,000 amino acids of human and rodent AKAP12 share 83% identity followed by about 600 amino acids with less than 20% identity. The N-terminal homology domain (green) shows about 40% identity to the Xgl (Xenopus gravin-like) gene in Xenopus. Both human and rodent AKAP12 share a shorter C-terminal domain containing the PKA-RII binding (AKAP) domain (green box in human AKAP12).

AKAP12 is phosphorylated by PLK1 on T766 during metaphase, and shRNa knockdown of AKAP12 leads to cytokinesis failure (Canton et al., 2012).

Left- Oncomine analysis (http://www.oncomine.org) of Lapointe prostate cancer expression data (Proc Natl Acad Sci U S A 2004;101:811-6) showing AKAP12 downregulation in human prostate cancer metastasis compared with levels in primary prostate cancer (1 prostate cancer) or normal prostate tissue. F, Kaplan-Meier plot analysis (http://www.cbioportal.org/public-portal/) of metastasis occurrence vs. time to onset in 37 prostate cancer metastasis cases from Taylor et al., 2010 in which 11 cases (29.7%) displayed AKAP12 downregulation compared with levels in primary prostate cancer lesions versus 26 cases with no change in AKAP12 levels.

A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient. Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (q < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Furthermore, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methylation status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression-free and overall survival in SOC patients. [from Bateman et al., 2015].