Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Golubkov, Vladislav S.; Strongin, Alex Y.

doi:10.1186/1478-811x-12-15

Cited by 26 publications

(27 citation statements)

References 43 publications

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“…Therefore, differences in the composition of the PTK7 co-receptor complex may explain these contradictory findings in different tissue settings. This is also supported by reports concerning PTK7 downstream signaling, where various signaling outcomes like activation of c-jun, AKT, Ras/ERK, CREB/ATF1, SRC and inhibition of JNK signaling were observed [ 39 , 40 , 41 , 42 ]. The fact that PTK7 interacts with other receptors like Plexin and VEGF receptors further supports this hypothesis and suggests that PTK7 is a versatile co-receptor [ 43 ].…”

Section: Introductionsupporting

confidence: 82%

A PTK7/Ror2 Co-Receptor Complex Affects Xenopus Neural Crest Migration

et al. 2015

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Neural crest cells are a highly migratory pluripotent cell population that generates a wide array of different cell types and failure in their migration can result in severe birth defects and malformation syndromes. Neural crest migration is controlled by various means including chemotaxis, repellent guidance cues and cell-cell interaction. Non-canonical Wnt PCP (planar cell polarity) signaling has previously been shown to control cell-contact mediated neural crest cell guidance. PTK7 (protein tyrosine kinase 7) is a transmembrane pseudokinase and a known regulator of Wnt/PCP signaling, which is expressed in Xenopus neural crest cells and required for their migration. PTK7 functions as a Wnt co-receptor; however, it remains unclear by which means PTK7 affects neural crest migration. Expressing fluorescently labeled proteins in Xenopus neural crest cells we find that PTK7 co-localizes with the Ror2 Wnt-receptor. Further, co-immunoprecipitation experiments demonstrate that PTK7 interacts with Ror2. The PTK7/Ror2 interaction is likely relevant for neural crest migration, because Ror2 expression can rescue the PTK7 loss of function migration defect. Live cell imaging of explanted neural crest cells shows that PTK7 loss of function affects the formation of cell protrusions as well as cell motility. Co-expression of Ror2 can rescue these defects. In vivo analysis demonstrates that a kinase dead Ror2 mutant cannot rescue PTK7 loss of function. Thus, our data suggest that Ror2 can substitute for PTK7 and that the signaling function of its kinase domain is required for this effect.

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Section: Introductionsupporting

confidence: 82%

A PTK7/Ror2 Co-Receptor Complex Affects Xenopus Neural Crest Migration

et al. 2015

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“…Ptk7 has additionally been linked to breast cancer [ 47 , 48 , 49 ] and leukemia [ 50 , 51 , 52 , 53 ]. Recently, Ptk7 was implicated in cancer cell motility and metastasis in fibrosarcoma HT1080 cells, identified as a potential diagnostic biomarker for a variety of cancer types [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], and proposed as a tumor suppressor gene by inhibiting ERK and AKT phosphorylation in lung cancer [ 39 ].…”

Section: The Transmembrane Receptor Ptk7mentioning

confidence: 99%

“…In addition, much like the invertebrate function of Otk, in vertebrate development, Ptk7 interacts with plexin A1 regulating neural crest migration [ 70 , 71 , 72 ]. Ptk7 is cleaved by a membrane type matrix metalloprotease (MT1-MMP) affecting its function in both zebrafish and human development, and cancer cell metastasis [ 61 , 73 , 74 , 75 , 76 ]. Taken together, these findings suggest that Ptk7 is a highly regulated, polarity-determining molecule in a variety of cellular behaviors both during development and in cancers.…”

Section: The Transmembrane Receptor Ptk7mentioning

confidence: 99%

Ptk7 and Mcc, Unfancied Components in Non-Canonical Wnt Signaling and Cancer

Dunn

Tolwinski

2016

Cancers

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Human development uses a remarkably small number of signal transduction pathways to organize vastly complicated tissues. These pathways are commonly associated with disease in adults if activated inappropriately. One such signaling pathway, Wnt, solves the too few pathways conundrum by having many alternate pathways within the Wnt network. The main or “canonical” Wnt pathway has been studied in great detail, and among its numerous downstream components, several have been identified as drug targets that have led to cancer treatments currently in clinical trials. In contrast, the non-canonical Wnt pathways are less well characterized, and few if any possible drug targets exist to tackle cancers caused by dysregulation of these Wnt offshoots. In this review, we focus on two molecules—Protein Tyrosine Kinase 7 (Ptk7) and Mutated in Colorectal Cancer (Mcc)—that do not fit perfectly into the non-canonical pathways described to date and whose roles in cancer are ill defined. We will summarize work from our laboratories as well as many others revealing unexpected links between these two proteins and Wnt signaling both in cancer progression and during vertebrate and invertebrate embryonic development. We propose that future studies focused on delineating the signaling machinery downstream of Ptk7 and Mcc will provide new, hitherto unanticipated drug targets to combat cancer metastasis.

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“…Recently, it was reported that PTK7, alone as well as in combination with MT1-MMP, ADAMs, and g-secretase, play important roles in cancer cell migration [38]. Additionally, both the PTK7 silencing and overexpression fully blocked the ability of fibrosarcoma HT1080 cells to metastasize to the lungs in nude mice and diminished productive cell invasion in a chick embryo model [39].…”

Section: Discussionmentioning

confidence: 98%