MYO1D binds with kinase domain of the EGFR family to anchor them to plasma membrane before their activation and contributes carcinogenesis

Ko, Yoo-Seung; Bae, Jeong A; Kim, Keon Young; Kim, Sung Jin; Sun, Eun Gene; Lee, Kyung Hwa; Kim, Nacksung; Kang, Hyeonggon; Seo, Young-Woo; Kim, Hangun; Chung, Ik Joo; Kim, Kyung Keun

doi:10.1038/s41388-019-0954-8

Cited by 19 publications

(25 citation statements)

References 47 publications

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“…Specifically, MYO1D was shown to directly interact with epidermal growth factor receptor (EGFR) and promote retention of this receptor at the plasma membrane. Such prolonged plasma membrane accumulation accelerated EGFR activity in MYO1D-overexpressing CRC cells, thereby increasing their tumorigenic features [52]. This data suggests that either lowering overexpression or inhibiting activity of MYO1D could have therapeutic potential in a subtype of CRC with high expression of EGFR family members and could also help to overcome tumor resistance to anti-EGFR therapy.…”

Section: Unconventional Myosins 31 Class I Myosinsmentioning

confidence: 89%

“…A recent study implicated another member of the myosin I family, MYO1D, in the regulation of CRC development [52]. In contrast to MYO1A, MYO1D protein expression was found to be upregulated in the advanced stages III and IV of CRC, although its association with patient survival has not been established [52]. Overexpression of MYO1D accelerates CRC cell invasion in vitro and promotes tumorigenesis in a syngeneic mouse xenograft model [52].…”

Section: Unconventional Myosins 31 Class I Myosinsmentioning

confidence: 99%

“…In contrast to MYO1A, MYO1D protein expression was found to be upregulated in the advanced stages III and IV of CRC, although its association with patient survival has not been established [52]. Overexpression of MYO1D accelerates CRC cell invasion in vitro and promotes tumorigenesis in a syngeneic mouse xenograft model [52]. Mechanisms of tumor-promoting activities of MYO1D are linked to regulation of growth factor receptor trafficking.…”

Section: Unconventional Myosins 31 Class I Myosinsmentioning

confidence: 99%

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Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Naydenov

Lechuga

Huang

et al. 2021

Cancers

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Colorectal cancer (CRC) remains the third most common cause of cancer and the second most common cause of cancer deaths worldwide. Clinicians are largely faced with advanced and metastatic disease for which few interventions are available. One poorly understood aspect of CRC involves altered organization of the actin cytoskeleton, especially at the metastatic stage of the disease. Myosin motors are crucial regulators of actin cytoskeletal architecture and remodeling. They act as mechanosensors of the tumor environments and control key cellular processes linked to oncogenesis, including cell division, extracellular matrix adhesion and tissue invasion. Different myosins play either oncogenic or tumor suppressor roles in breast, lung and prostate cancer; however, little is known about their functions in CRC. This review focuses on the functional roles of myosins in colon cancer development. We discuss the most studied class of myosins, class II (conventional) myosins, as well as several classes (I, V, VI, X and XVIII) of unconventional myosins that have been linked to CRC development. Altered expression and mutations of these motors in clinical tumor samples and their roles in CRC growth and metastasis are described. We also evaluate the potential of using small molecular modulators of myosin activity to develop novel anticancer therapies.

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Section: Unconventional Myosins 31 Class I Myosinsmentioning

confidence: 89%

Section: Unconventional Myosins 31 Class I Myosinsmentioning

confidence: 99%

Section: Unconventional Myosins 31 Class I Myosinsmentioning

confidence: 99%

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Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Naydenov

Lechuga

Huang

et al. 2021

Cancers

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“…Previously, we provided the first evidence that the molecular motor MYO1D helps to maintain cell‐surface ErbB receptor levels (except ErbB3) by holding the receptor to the plasma membrane. 8 Here, we evaluated whether MYO1D also holds mutant EGFRs on the NSCLC cell surface and whether blockade of MYO1D function affects the proliferation and survival of NSCLC cells with variable resistance to existing anti‐ErbB agents.…”

mentioning

confidence: 99%

“…As we previously identified that the kinase domain (KD) of EGFR was needed for binding of MYO1D to EGFR in colorectal cancer (CRC) cells, 8 we first checked whether the ATP‐binding region within the KD participates in the binding between MYO1D and EGFR in NSCLC cells. The KD is characterized by an N‐terminal ATP‐binding lobe (N‐lobe) and a C‐lobe.…”

mentioning

confidence: 99%

New strategy for suppressing the growth of lung cancer cells harboring mutations in the ATP‐binding region of EGFR by targeting the molecular motor MYO1D

Kang

Bae

et al. 2021

Clinical & Translational Med

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In this study, we describe that the molecular motor MYO1D holds both wild-type and mutant EGFRs in the plasma membrane via interaction of MYO1D with a C-terminal portion of the kinase domain (C-terminal substrate-binding lobe or C-lobe) that does not contain the ATP-binding region. Further, we show that the knockdown of MYO1D suppresses the growth, invasion and downstream signals of lung cancer and glioblastoma cells expressing mutant EGFR or mutant ErbB2, which have resistance to afatinib, osimertinib, and cetuximab. This represents a new strategy of reducing the wild-type and mutant EGFRs themselves to treat acquired resistance in various EGFR-overexpressing cancers harboring mutations in the ATP-binding region, which is directly targeted by most tyrosine kinase inhibitors (TKIs).The main challenge during EGFR-targeted therapy in nonsmall cell lung cancer (NSCLC) is the acquisition of resistance to EGFR-TKIs. 1 Mechanisms of therapeutic resistance include mutations of the kinase domain at the T790M or C797S codon that interfere with TKI access to the active site, which is difficult to treat with standard therapeutic options. 2,3 The EGFR (ErbB1) and ErbB2 pathways are functionally linked and pivotal in the progression of NSCLC. 1 Overexpression of ErbB2 has been reported in about 20% of lung cancers in which mutant ErbB2 is more potent than the wild type in promoting tumorigenicity. 4,5 Thus, combined inhibition of ErbB receptors could prevent a molecular feedback loop responsible for acquired resistance to existing anti-ErbB agents. 6,7 To this aim, a new strategy can be considered: a single multitargeted agent and a new class of anti-ErbB agent with a different molecular mechanism.

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Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin type‐B receptor 4

Zhu

Wang

et al. 2022

Molecular Oncology

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The oncogenic role of ephrin type‐B receptor 4 (EPHB4) has been reported in many types of tumors, including chronic myeloid leukemia (CML). Here, we found that CML patients have a higher EPHB4 expression level than healthy subjects. EPHB4 knockdown inhibited growth of K562 cells (a human immortalized myelogenous leukemia cell line). In addition, transient transfection of EPHB4 siRNA led to sensitization to imatinib. These growth defects could be fully rescued by EPHB4 transfection. To identify an EPHB4‐specific inhibitor with the potential of rapid translation into the clinic, a pool of clinical compounds was screened and vandetanib was found to be most sensitive to K562 cells, which express a high level of EPHB4. Vandetanib mainly acts on the intracellular tyrosine kinase domain and interacts stably with a hydrophobic pocket. Furthermore, vandetanib downregulated EPHB4 protein via the ubiquitin‐proteasome pathway and inhibited PI3K/AKT and MAPK/ERK signaling pathways in K562 cells. Vandetanib alone significantly inhibited tumor growth in a K562 xenograft model. Furthermore, the combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib‐resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via targeting EPHB4.

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MYO1D binds with kinase domain of the EGFR family to anchor them to plasma membrane before their activation and contributes carcinogenesis

Cited by 19 publications

References 47 publications

Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

New strategy for suppressing the growth of lung cancer cells harboring mutations in the ATP‐binding region of EGFR by targeting the molecular motor MYO1D

Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin type‐B receptor 4

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