Biological influence of Hakai in cancer: a 10-year review

Abstract

In order to metastasize, cancer cells must first detach from the primary tumor, migrate, invade through tissues, and attach to a second site. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells that is characterized as a potent tumor suppressor and is modulated during various processes including epithelial-mesenchymal transition. Recent data have provided evidences for novel biological functional role of Hakai during tumor progression and other diseases. Here, we will review the knowledge that has been accumulated since Hakai discovery 10 years ago and its implication in human cancer disease. We will highlight the different signaling pathways leading to the influence on Hakai and suggest its potential usefulness as therapeutic target for cancer.

Fig. 1

Posttranslational mechanism to donwregulate E-cadherin at AJ by Hakai. a Epithelial phenotype. E-cadherin contains five repetitive subdomains to conform the extracellular domain by which it forms homophilic interactions to the extracellular domain of the E-cadherin of the neighboring cell. Its cytoplasmic domain contains two sequences: CH2 domain that interact with p120-catenin and the CH3 domain interacting with β-catenin. It is also linked to the actin cytoeskeleton through the dynamic shuttling of α-catenin between cadherin/β-catenin and actin. b Fibroblastic-like phenotype induced by Hakai. After tyrosine phosphorylation by Src in the cytoplasmic domain of E-cadherin, Hakai induces the ubiquitination of the complex, following endocytosis into vesicles through the action of Rab5 and Rab7 to finally degrade into lysosomes, altering the integrity of cell–cell contacts

Fig. 2

A schematic domain structure of c-Cbl and Hakai proteins. a Domain structure of c-Cbl protein contain a phophotyrosin-binding domain (pTyr-B), a RING-finger domain, a proline-rich region, and a lucine zipper (Leu-Z) domain. b Molecular structure of E3 ubiquitin-ligase Hakai. A novel domain, HYB (Hakai pTyr-binding) consist of a pair of monomers arranged in an anti-parallel configuration. Each monomer consists of two zinc-finger domains: a RING finger domain and a short pTyr-B domain that incorporates a novel, atypical Zn-finger coordination motif. Both domains are important for dimerization

Fig. 3

Hakai upstream signaling pathways. a Ca²⁺ depletion activate Cdc42 to initiate activation of EGFR and Src, which in turn phosphorylate E-cadherin, leading Hakai-mediated E-cadherin ubiquitination and degradation. The inhibition of Rack1 of the epithelial cell–cell adhesions by regulating Src and growth factor induced endocytosis of E-cadherin. b TGFβ and Raf signaling crosstalk to regulate EMT at posttranslational through E-cadherin ubiquitination and degradation. c Slit-Robo signaling induces malignant transformation during colorectal cell carcinogenesis through Hakai-mediated E-cadherin degradation