KIF1C facilitates retrograde transport of lysosomes through Hook3 and dynein.

Lysosomes, crucial cellular organelles, undergo bidirectional transport along microtubules, mediated by motor proteins such as cytoplasmic dynein-1 (dynein) and various kinesins. While the kinesin-3 family member KIF1C is established in mediating anterograde vesicle transport, its role in lysosomal transport remains unclear. Our study reveals that KIF1C unexpectedly supports the retrograde transport of lysosomes, driven by dynein, and contributes to their perinuclear localization.

Role of the Ror family receptors in Wnt5a signaling.

Ror-family receptors, Ror1 and Ror2, are type I transmembrane proteins that possess an extracellular cysteine-rich domain, which is conserved throughout the Frizzled-family receptors and is a binding site for Wnt ligands. Both Ror1 and Ror2 function primarily as receptors or co-receptors for Wnt5a to activate the β-catenin-independent, non-canonical Wnt signaling, thereby regulating cell polarity, migration, proliferation, and differentiation depending on the context. Ror1 and Ror2 are expressed highly in many tissues during embryogenesis but minimally or scarcely in adult tissues, with some exceptions.

miR-200c-141 induces a hybrid E/M state and promotes collective cell migration in MDA-MB-231 cells.

The microRNA-200 (miR-200) family is a potent suppressor of epithelial-to-mesenchymal transition (EMT). While its role as a tumor suppressor has been well documented, recent studies suggested that it can promote cancer progression in several stages. In this study, we investigated whether the miR-200 family members play a role in the acquisition of a hybrid epithelial/mesenchymal (E/M) state, which is reported to be associated with cancer malignancy, in mesenchymal MDA-MB-231 cells.

Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression.

Rho in filopodia (Rif), a member of the Rho family of small GTPases, induces filopodia formation primarily on the dorsal surface of cells; however, its function remains largely unclear. Here, we show that Rif interacts with Ror1, a receptor for Wnt5a that can also induce dorsal filopodia. Our immunohistochemical analysis revealed a high frequency of coexpression of Ror1 and Rif in lung adenocarcinoma.

c-Src-mediated phosphorylation and activation of kinesin KIF1C promotes elongation of invadopodia in cancer cells.

Invadopodia on cancer cells play crucial roles in tumor invasion and metastasis by degrading and remodeling the surrounding extracellular matrices and driving cell migration in complex 3D environments. Previous studies have indicated that microtubules (MTs) play a crucial role in elongation of invadopodia, but not their formation, probably by regulating delivery of membrane and secretory proteins within invadopodia. However, the identity of the responsible MT-based molecular motors and their regulation has been elusive.

Autonomous and intercellular chemokine signaling elicited from mesenchymal stem cells regulates migration of undifferentiated gastric cancer cells.

Accumulating evidence demonstrates that bone marrow (BM)-derived mesenchymal stem cells (MSCs) play critical roles in regulating progression of various types of cancer. We have previously shown that Wnt5a-Ror2 signaling in MSCs induces expression of CXCL16, and that CXCL16 secreted from MSCs then binds to its cognate receptor CXCR6 on the surface of an undifferentiated gastric cancer cell line MKN45 cells, eventually leading to proliferation and migration of MKN45 cells. However, it remains unclear about a possible involvement of another (other) cytokine(s) in regulating progression of gastric cancer.

Characterization of morphological alterations in micropapillary adenocarcinoma of the lung using an established cell line.

Micropapillary adenocarcinoma of the lung is a type of cancer associated with a poor prognosis and is characterized by the presence of tumor cells with a ring‑like glandular structure floating within alveolar spaces. In the present study, the association between its morphological, biochemical and immunohistochemical characteristics, and malignancy was investigated using the KU‑Lu‑MPPt3 cell line established from a patient with MIP adenocarcinoma. Two subpopulations of KU‑Lu‑MPPt3 cells, namely adhesive (AD) and clumpy and suspended (CS) cells, were prepared and subjected to DNA microarray, reverse transcription‑quantitative PCR, western blot and immunostaining analyses.

Stage-dependent function of Wnt5a during male external genitalia development.

External genitalia development in mice involves multiple developmental processes under the regulation of various signaling pathways. Wnt5a, one of the major Wnt ligands, is a crucial developmental regulator of outgrowing organs such as the limb, the mandible, and the external genitalia. Defects in Wnt5a signaling have been linked to Robinow syndrome, a genetic disorder in which male patients manifest a micropenis and defective urethral tube formation.

Oncogenic E6 and/or E7 proteins drive proliferation and invasion of human papilloma virus‑positive head and neck squamous cell cancer through upregulation of Ror2 expression.

Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)‑positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV‑related cancers. However, the function of Ror2 in HPV‑positive HNSCC is currently unknown.

Mesenchymal stem cell-derived CXCL16 promotes progression of gastric cancer cells by STAT3-mediated expression of Ror1.

Bone marrow-derived mesenchymal stem or stromal cells (MSC) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSC, and Wnt5a-Ror2 signaling in MSC induces expression of CXCL16, which, in turn, promotes proliferation of co-cultured MKN45 gastric cancer cells via the CXCL16-CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells.

Tactics of cancer invasion: solitary and collective invasion.

Much attention has been paid on the mechanism of cancer invasion from the viewpoint of the behaviour of individual cancer cells. On the other hand, histopathological analyses of specimens from cancer patients and of cancer invasion model animals have revealed that cancer cells often exhibit collective invasion, characterized by sustained cell-to-cell adhesion and polarized invasion as cell clusters. Interestingly, it has recently become evident that during collective invasion of cancer cells, the cells localized at invasion front (leader cells) and the cells following them (follower cells) exhibit distinct cellular characteristics, and that there exist the cells expressing representative proteins related to both epithelial and mesenchymal properties simultaneously, designated as hybrid epithelial-to-mesenchymal transition (EMT)-induced cells, in cancer tissue.

Impaired ligand-dependent MET activation caused by an extracellular SEMA domain missense mutation in lung cancer.

Aberrant activation of the MET/hepatocyte growth factor (HGF) receptor participates in the malignant behavior of cancer cells, such as invasion-metastasis and resistance to molecular targeted drugs. Many mutations in the MET extracellular region have been reported, but their significance is largely unknown. Here, we report the dysregulation of mutant MET originally found in a lung cancer patient with Val370 to Asp370 (V370D) replacement located in the extracellular SEMA domain.

[Non-canonical Wnt signaling and cellular responses.].

Non-canonical Wnt signaling, including planar cell polarity and Ca pathways, plays crucial roles in developmental processes, including morphogenesis and tissue-/organo-genesis, in animals. Ror2 receptor tyrosine kinase mediates non-canonical Wnt signaling by acting as a receptor for Wnt5a, which also inhibits canonical Wnt signaling. Dysregulation of Wnt5a-Ror2 signaling causes a wide range of developmental defects and cancer progression.

Genetic interactions between Ror2 and Wnt9a, Ror1 and Wnt9a and Ror2 and Ror1: Phenotypic analysis of the limb skeleton and palate in compound mutants.

Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2 mutant mice. In contrast, Ror1 mutant mice are viable and show no limb phenotype.

Intraflagellar transport 20 promotes collective cancer cell invasion by regulating polarized organization of Golgi-associated microtubules.

Collective invasion is an important strategy of cancers of epithelial origin, including colorectal cancer (CRC), to infiltrate efficiently into local tissues as collective cell groups. Within the groups, cells at the invasive front, called leader cells, are highly polarized and motile, thereby providing the migratory traction that guides the follower cells. However, its underlying mechanisms remain unclear.

Synchronized mesenchymal cell polarization and differentiation shape the formation of the murine trachea and esophagus.

Tube morphogenesis is essential for internal-organ development, yet the mechanisms regulating tube shape remain unknown. Here, we show that different mechanisms regulate the length and diameter of the murine trachea. First, we found that trachea development progresses via sequential elongation and expansion processes.

Critical role of the Ror-family of receptor tyrosine kinases in invasion and proliferation of malignant pleural mesothelioma cells.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis and closely related to exposure to asbestos. MPM is a heterogeneous tumor with three main histological subtypes, epithelioid, sarcomatoid, and biphasic types, among which sarcomatoid type shows the poorest prognosis. The Ror-family of receptor tyrosine kinases, Ror1 and Ror2, is expressed in various types of tumor cells at higher levels and affects their aggressiveness.

Expression of Ror2 Associated with Fibrosis of the Submandibular Gland.

The submandibular gland (SMG) is one of the major salivary glands that play important roles for variety of physiological functions, such as digestion of foods, prevention of infection, and lubrication of the mouth. Dysfunction of the SMG, often associated with a salivary inflammation, adversely influences a person's quality of life. However, the mechanism underlying inflammation-driven dysfunction of the SMG is largely unknown.

Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling.

Cytoskeletal reorganization in osteoclasts to form actin rings is necessary for these cells to attach to bone and resorb bone matrices. We delineated the pathway through which Wnt5a signaling through receptor tyrosine kinase-like orphan receptor 2 (Ror2) promoted the bone-resorbing activity of osteoclasts. Wnt5a binding to Ror2 stimulated Rho, a small GTPase involved in cytoskeletal reorganization.

Regulatory mechanisms and cellular functions of non-centrosomal microtubules.

Proper organization of microtubule (MT) arrays is essential for numerous cellular functions, including intracellular transport and cell migration. Although the centrosome generally serves as the primary MT-organizing centre in proliferating animal cells, MTs are also organized at the Golgi apparatus in a wide range of cell types to regulate Golgi ribbon formation that is required for polarized cell migration. Furthermore, differentiated epithelial cells and neurons possess organized non-centrosomal MTs predominantly at the apical cortical regions and the axonal and dendritic neurites, respectively, to establish and maintain their highly polarized morphology.

Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness.

Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion.

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice.

Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy.

Essential role of Wnt5a-Ror1/Ror2 signaling in metanephric mesenchyme and ureteric bud formation.

Spatiotemporally regulated interaction between the metanephric mesenchyme (MM) and Wolffian duct (WD) is essential for the induction of a single ureteric bud (UB). The MM then interacts with the tip of the UB to induce outgrowth and branching of the UB, which in turn promotes growth of the adjacent MM. The Ror family receptor tyrosine kinases, Ror1 and Ror2, have been shown to act as receptors for Wnt5a to mediate noncanonical Wnt signaling.

Wnt5a-Ror2 signaling in mesenchymal stem cells promotes proliferation of gastric cancer cells by activating CXCL16-CXCR6 axis.

Wnt5a-Ror2 signaling has been shown to play important roles in promoting aggressiveness of various cancer cells in a cell-autonomous manner. However, little is known about its function in cancer-associated stromal cells, including mesenchymal stem cells (MSCs). Thus, we examined the role of Wnt5a-Ror2 signaling in bone marrow-derived MSCs in regulating proliferation of undifferentiated gastric cancer cells.

Insight into the role of Wnt5a-induced signaling in normal and cancer cells.

Wnt5a is involved in the activation of noncanonical Wnt signaling, including planar cell polarity (PCP) and Wnt-Ca(2+) pathways. The Ror-family of receptor tyrosine kinases is composed of Ror1 and Ror2 in mammals. Ror2 acts as a receptor or coreceptor for Wnt5a and regulates Wnt5a-induced activation of PCP pathway, and Wnt5a-Ror2 axis indeed plays critical roles in the developmental morphogenesis by regulating cell polarity and migration.