Kinase Family Ack

Kinase Classification: Group TK: Family Ack

Acks are cytoplasmic tyrosine kinases that bind and modulate receptor signaling through interaction with small GTPases.

Evolution

Ack genes are found in eumetazoans (non-sponge animals). They have varied domain combinations, typically with a SAM domain followed by the kinase domains, an SH3, and then a GTPase-interacting domain: either a PBD (in Drosophila PR2 and worm ark-1) or a GTPase_binding domain (in worm kin-25 and both vertebrate genes). Vertebrate Tnk1 has an unusual phylogenetic pattern: it is found in eutherian mammals, frogs, and fish, but not in reptiles, birds, or early-branching mammals. Further, the mammalian form has diverged in the C-terminal from the fish form, suggesting a shift in function.

Function

Human Ack (Ack1, TNK2) is the best-described member. It binds the small GTPase CDC42 in its GTPase-bound form and maintains it in this active conformation, enhancing its function in prolonging the activation of the EGFR pathway.

Ack genes have also been implicated in integrin signaling and clathrin-mediated endocytosis. Human Ack can phosphorylate Akt, leading to its membrane association and activation [1].

Tnk1 is a vertebrate paralog of Ank. The mouse knockout a high rate of tumors, even in heterozygotes, where the promoter of the remaining allele is hypermethylated [2]. In cell lines, it acts as a supressor of Ras signaling [3]. Knockout cells have higher Ras activity due to an increase in Ras GEF activity. Tnk1 phosphorylates Grb2, causing dissociation of the Grb2-Sos1 complex and so blocking ras activation. Human Tnk1 has also been implicated in Alzheimer's Disease, and can block the activation of NK-kappaB by TNFalpha signaling by an unknown mechanism [4].

Drosophila PR2 and C. elegans ark-1 form a distinct subfamily of Ack proteins, with a PBD domain in place of the analogous GTPase_binding domain. Homologs are found in other metazoans, including amphioxus, but not in vertebrates.

PR2 binds the receptor phosphatase PTP96A and may modulate axon outgrowth through ras (http://hdl.handle.net/1721.1/32254). It may also synergize with dpp (TGF-beta) signaling in dorsal closure during development. [5]

ark-1 is known as an inhibitor of EGFR/ras signaling during vulval development. It binds the Grb2 homolog, sem-5, and both ark-1 and sem-5 are also involved in modulating IP3 signaling downstream of EGFR. [6]

References

1. Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schönbrunn E, Sebti SM, Earp HS, and Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. DOI:10.1371/journal.pone.0009646 |
2. Hoare S, Hoare K, Reinhard MK, Lee YJ, Oh SP, and May WS Jr. Tnk1/Kos1 knockout mice develop spontaneous tumors. Cancer Res. 2008 Nov 1;68(21):8723-32. DOI:10.1158/0008-5472.CAN-08-1467 |
3. Hoare K, Hoare S, Smith OM, Kalmaz G, Small D, and Stratford May W. Kos1, a nonreceptor tyrosine kinase that suppresses Ras signaling. Oncogene. 2003 Jun 5;22(23):3562-77. DOI:10.1038/sj.onc.1206480 |
4. Azoitei N, Brey A, Busch T, Fulda S, Adler G, and Seufferlein T. Thirty-eight-negative kinase 1 (TNK1) facilitates TNFalpha-induced apoptosis by blocking NF-kappaB activation. Oncogene. 2007 Oct 4;26(45):6536-45. DOI:10.1038/sj.onc.1210476 |
5. Zahedi B, Shen W, Xu X, Chen X, Mahey M, and Harden N. Leading edge-secreted Dpp cooperates with ACK-dependent signaling from the amnioserosa to regulate myosin levels during dorsal closure. Dev Dyn. 2008 Oct;237(10):2936-46. DOI:10.1002/dvdy.21722 |
6. Moghal N and Sternberg PW. The epidermal growth factor system in Caenorhabditis elegans. Exp Cell Res. 2003 Mar 10;284(1):150-9. DOI:10.1016/s0014-4827(02)00097-6 |