Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br ACK signaling partners ACK

    2023-01-28


    ACK1 signaling partners ACK1 interacts with and tyrosine phosphorylates many cellular proteins regulating critical cellular processes [11]. While ACK1 shares common intracellular effectors such as AKT with other signaling pathways, it imparts specificity to signaling by phosphorylating effectors at distinct sites [11], [14]. Majority of the sites that ACK1 phosphorylates are strikingly unique, which includes AKT at Tyr176, androgen receptor or AR at Tyr267 and Tyr363 and the tumor suppressor Wwox at Tyr287 [11]. This feature is attributed to the unusual peptide substrate binding ability of ACK1 [38]. The significance of ACK1 interactome in cancer cell survival acquired significance due to our understanding of many of its preferred substrates and their activation. For a comprehensive description of all ACK1 interacting proteins, detailed information is available from other reviews [11], [15], [26].
    ACK1 stabilization in cancers While in normal cells, such as mouse embryo fibroblast cell lines, ACK1 activation is rapid and transient in response to EGFR stimulation, several cancer AZD3514 show constitutive activation of ACK1. One mechanism by which normal cells switch off ACK1 activation is by ubiquitin mediated degradation of the protein, likely facilitated by the UBA domains at the carboxy-terminus of the protein [45], [46]. In support of this finding, an ACK1 S985N mutant, located in the ubiquitin association domain (UBA) and identified in a renal carcinoma cell line, is defective in ubiquitin binding and appears to stabilize ACK1 protein levels [24]. Further, ACK1 S985N mutation promotes cell proliferation, migration and anchorage-independent growth as well as the epithelial–mesenchymal transition. Consistent with the above observations, over-expression of ACK1 in human cervical cancer derived cell line, HeLa, confined EGFR to early endosomes and prevented sorting to other vesicles for degradation [47]. Indeed, the resistance to EGFR inhibitor, gefitinib, has been suggested to work via preventing EGF-EGFR trafficking out of early endosomes toward the late endosomes/lysosomes [48]. Not surprisingly, loss of ACK1 sensitized the EGFR inhibitor gefitinib resistant renal carcinoma cells to cell death. Thus, combined inhibition of both EGFR and ACK1 could be a novel chemotherapeutic strategy to overcome gefitinib resistance [24], [25]. Notably, ACK1 co-localizes with the E3 ubiquitin ligase NEDD4-2 in clathrin-rich vesicles [45]. The proline-rich sequences in ACK1 interact with WW domain of NEDD4-2. Interestingly, ACK1 uses the same region to interact with the tumor suppressor Wwox [12]. This process is tightly regulated as it requires EGFR-mediated ACK1 activation to drive kinase degradation by NEDD4-2 [45]. Comparing the binding of NEDD4-1 and NEDD4-2 to ACK1, Lin et al., observed that although the two ubiquitin ligases bound similarly to ACK1, the difference in ubiquitylation of ACK1 mediated by NEDD4-1 was more than 10-fold, suggesting some degree of specificity [46]. Indeed, the Tyr650 in ACK1 seems to be essential for interaction with NEDD4-1. Future cancer genome sequencing efforts may uncover mutations in ubiquitin ligases themselves that block ACK1 degradation and thus stabilize ACK1 to promote oncogenesis. In contrast to EGF stimulated ACK1 degradation, ACK1 is found to be degraded in a kinase independent fashion by the Seven in absentia homolog (SIAH) ubiquitin ligases, SIAH1 and 2 [49]. These ligases interact with ACK1 via a highly conserved SIAH-binding motif located at the C-terminal proline rich region of ACK1. A point mutation in the C terminus abolished the interaction of ACK1 with SIAH ligases. SIAH2 mediates the ubiquitylation of ACK1 for proteolysis by the proteasome machinery in estrogen (E2) stimulated breast cancer cells. Furthermore, SIAH2 may be a target gene of E2 in breast cancer cells. This work has significant implications particularly for triple negative breast cancers (TNBCs). Since degradation of ACK1 depends on intact E2/ER (estrogen receptor) signaling, TNBCs that lack ER could potentially increase stability of ACK1 and thus likely to be important in promoting breast cancer survival and metastasis.