AKAP4 explained

A-kinase anchor protein 4 is a scaffold protein that in humans is encoded by the AKAP4 gene.^{[1] [2] [3]} It involves in the intracellular signalling of protein kinase -A.^[4] AKAP4 is called as cancer /testis antigen (CTA), it belongs to a class of tumour linked antigens categories by high expression in germ cells and cancer than normal tissues.^[5] AKAP4 is not normally expressed in mRNA and protein level in MM cell line.^[6]

Function

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is localized to the sperm flagellum and may be involved in the regulation of sperm motility. Alternative splicing of this gene results in two transcript variants encoding different isoforms.

AKAP 4 protein belongs to the family of scaffold proteins and is involved in controlled mechanism of flagellar function.^[7] In mice, AKAP4 is required for sperm development and male mice that lack AKAP4 are infertiel The fibrous sheath was not formed, flagellum become short and often some proteins associated with the fibrous sheath in this case they were very few or absent. Surprisingly, another component of flagellum was developed as normal. In the conclusion, they state that AKAP4 plays a pivotal role in the fibrous sheath and effect on the motility of sperm, in the absence of AKAP4 these activities affected due to a failure of signal transduction and glycolytic enzymes because they were not able to attach with the fibrous sheath.

Clinical significance

AKAP4 is a potential biomarker for early diagnosis and immunotherapy of colon cancer.^[8] AKAP4 may be implicated as a biomarker and immunotherapeutic target for cervical cancer.^[9] AKAP4 is also a circulating biomarker for non-small cell lung cancer.^[10] To detect the early stage breast cancer and diagnosis, AKAP4 is used as serum. Investigation was undertaken about AKAP4 with various clinical parameters which could be use as early detector biomarker to treat cancer by developing a tissue or serum.

AKAP4 is associated with diseases such as multiple myeloma, lung cancer, breast cancer and prostate cancer.^[11]

AKAP4 is over expressed in multiple myeloma (MM)^[12]

Interactions

AKAP4 has been shown to interact with:

• AKAP3, and
• PRKAR1A.^{[13] [14]}

Further reading

• Lester LB, Scott JD . Anchoring and scaffold proteins for kinases and phosphatases . Recent Progress in Hormone Research . 52 . 409–29; discussion 429–30 . 1997 . 9238861 .
• Michel JJ, Scott JD . AKAP mediated signal transduction . Annual Review of Pharmacology and Toxicology . 42 . 235–57 . 2002 . 11807172 . 10.1146/annurev.pharmtox.42.083101.135801 .
• Miki K, Eddy EM . Identification of tethering domains for protein kinase A type Ialpha regulatory subunits on sperm fibrous sheath protein FSC1 . The Journal of Biological Chemistry . 273 . 51 . 34384–90 . December 1998 . 9852104 . 10.1074/jbc.273.51.34384 . free .
• Turner RM, Foster JA, Gerton GL, Moss SB, Patrizio P . Molecular evaluation of two major human sperm fibrous sheath proteins, pro-hAKAP82 and hAKAP82, in stump tail sperm . Fertility and Sterility . 76 . 2 . 267–74 . August 2001 . 11476771 . 10.1016/S0015-0282(01)01922-7 . free .
• Ficarro S, Chertihin O, Westbrook VA, White F, Jayes F, Kalab P, Marto JA, Shabanowitz J, Herr JC, Hunt DF, Visconti PE . Phosphoproteome analysis of capacitated human sperm. Evidence of tyrosine phosphorylation of a kinase-anchoring protein 3 and valosin-containing protein/p97 during capacitation . The Journal of Biological Chemistry . 278 . 13 . 11579–89 . March 2003 . 12509440 . 10.1074/jbc.M202325200 . free .
• Brown PR, Miki K, Harper DB, Eddy EM . A-kinase anchoring protein 4 binding proteins in the fibrous sheath of the sperm flagellum . Biology of Reproduction . 68 . 6 . 2241–8 . June 2003 . 12606363 . 10.1095/biolreprod.102.013466 . free .
• Lefièvre L, Chen Y, Conner SJ, Scott JL, Publicover SJ, Ford WC, Barratt CL . Human spermatozoa contain multiple targets for protein S-nitrosylation: an alternative mechanism of the modulation of sperm function by nitric oxide? . Proteomics . 7 . 17 . 3066–84 . September 2007 . 17683036 . 2777308 . 10.1002/pmic.200700254 .
• Moretti E, Scapigliati G, Pascarelli NA, Baccetti B, Collodel G . Localization of AKAP4 and tubulin proteins in sperm with reduced motility . Asian Journal of Andrology . 9 . 5 . 641–9 . September 2007 . 17712481 . 10.1111/J.1745-7262.2007.00267.X . free .

Notes and References

1. Turner RM, Johnson LR, Haig-Ladewig L, Gerton GL, Moss SB . An X-linked gene encodes a major human sperm fibrous sheath protein, hAKAP82. Genomic organization, protein kinase A-RII binding, and distribution of the precursor in the sperm tail . The Journal of Biological Chemistry . 273 . 48 . 32135–41 . November 1998 . 9822690 . 10.1074/jbc.273.48.32135 . free .
2. Mohapatra B, Verma S, Shankar S, Suri A . Molecular cloning of human testis mRNA specifically expressed in haploid germ cells, having structural homology with the A-kinase anchoring proteins . Biochemical and Biophysical Research Communications . 244 . 2 . 540–5 . March 1998 . 9514854 . 10.1006/bbrc.1998.8079 .
3. Web site: Entrez Gene: AKAP4 A kinase (PRKA) anchor protein 4.
4. Turner RM, Musse MP, Mandal A, Klotz K, Jayes FC, Herr JC, Gerton GL, Moss SB, Chemes HE . Molecular genetic analysis of two human sperm fibrous sheath proteins, AKAP4 and AKAP3, in men with dysplasia of the fibrous sheath . Journal of Andrology . 22 . 2 . 302–15 . March 2001 . 10.1002/j.1939-4640.2001.tb02184.x . 11229805 .
5. Chiriva-Internati M, Cobos E, Da Silva DM, Kast WM . Sperm fibrous sheath proteins: a potential new class of target antigens for use in human therapeutic cancer vaccines . Cancer Immunity . 8 . 8 . April 2008 . 18433090 . 2935778 .
6. Chiriva-Internati M, Ferrari R, Yu Y, Hamrick C, Gagliano N, Grizzi F, Frezza E, Jenkins MR, Hardwick F, D'Cunha N, Kast WM, Cobos E . AKAP-4: a novel cancer testis antigen for multiple myeloma . British Journal of Haematology . 140 . 4 . 465–8 . February 2008 . 18217892 . 10.1111/j.1365-2141.2007.06940.x . 31138294 . free .
7. Miki K, Willis WD, Brown PR, Goulding EH, Fulcher KD, Eddy EM . Targeted disruption of the Akap4 gene causes defects in sperm flagellum and motility . Developmental Biology . 248 . 2 . 331–42 . August 2002 . 12167408 . 10.1006/dbio.2002.0728 . free .
8. Jagadish N, Parashar D, Gupta N, Agarwal S, Sharma A, Fatima R, Suri V, Kumar R, Gupta A, Lohiya NK, Suri A . A novel cancer testis antigen target A-kinase anchor protein (AKAP4) for the early diagnosis and immunotherapy of colon cancer . Oncoimmunology . 5 . 2 . e1078965 . February 2016 . 27057472 . 4801464 . 10.1080/2162402X.2015.1078965 .
9. Agarwal S, Saini S, Parashar D, Verma A, Jagadish N, Batra A, Suri S, Bhatnagar A, Gupta A, Ansari AS, Lohiya NK, Suri A . Expression and humoral response of A-kinase anchor protein 4 in cervical cancer . International Journal of Gynecological Cancer . 23 . 4 . 650–8 . May 2013 . 23478221 . 10.1097/IGC.0b013e31828a0698 . 205679790 .
10. Gumireddy K, Li A, Chang DH, Liu Q, Kossenkov AV, Yan J, Korst RJ, Nam BT, Xu H, Zhang L, Ganepola GA, Showe LC, Huang Q . AKAP4 is a circulating biomarker for non-small cell lung cancer . Oncotarget . 6 . 19 . 17637–47 . July 2015 . 26160834 . 4627334 . 10.18632/oncotarget.3946 .
11. Saini S, Jagadish N, Gupta A, Bhatnagar A, Suri A . A novel cancer testis antigen, A-kinase anchor protein 4 (AKAP4) is a potential biomarker for breast cancer . PLOS ONE . 8 . 2 . e57095 . 2013-02-22 . 23451156 . 3579772 . 10.1371/journal.pone.0057095 . 2013PLoSO...857095S . free .
12. Shankar S, Mohapatra B, Suri A . Cloning of a novel human testis mRNA specifically expressed in testicular haploid germ cells, having unique palindromic sequences and encoding a leucine zipper dimerization motif . Biochemical and Biophysical Research Communications . 243 . 2 . 561–5 . February 1998 . 9480848 . 10.1006/bbrc.1997.7943 .
13. Brown PR, Miki K, Harper DB, Eddy EM . A-kinase anchoring protein 4 binding proteins in the fibrous sheath of the sperm flagellum . Biology of Reproduction . 68 . 6 . 2241–8 . June 2003 . 12606363 . 10.1095/biolreprod.102.013466 . free .
14. Miki K, Eddy EM . Identification of tethering domains for protein kinase A type Ialpha regulatory subunits on sperm fibrous sheath protein FSC1 . The Journal of Biological Chemistry . 273 . 51 . 34384–90 . December 1998 . 9852104 . 10.1074/jbc.273.51.34384 . free .