Differential induction of glioblastoma migration and growth by two forms of pleiotrophin.
Glioblastoma is the most common malignant brain tumor of adults and one of the most lethal cancers. The secreted growth factor pleiotrophin (PTN) promotes glioblastoma migration and proliferation, initiating its oncogenic activities through two cell surface receptors, the protein tyrosine phosphatase receptor zeta (PTPRZ1) and the anaplastic lymphoma kinase (ALK), respectively. Here, we report on the presence and purification of two naturally occurring forms of PTN (18 and 15 kDa) that differentially promote glioblastoma migration and proliferation. Using a panel of glioblastoma cell lines, including low passage patient-derived cultures, we demonstrate that PTN15 promotes glioblastoma proliferation in an ALK-dependent fashion, whereas immobilized PTN18 promotes haptotactic migration of glioblastoma cells in a PTPRZ1-dependent fashion. Mass spectrometric analysis indicated that PTN15 differs from PTN18 by processing of 12 C-terminal amino acids. To demonstrate clinical relevance, we show that PTN15, PTN18, and PTPRZ1 are significantly overexpressed in glioblastoma relative to normal brain at both mRNA and protein levels using microarray, Western blot, and tissue microarray analyses on human tumors. These results indicate that the PTN18-PTPRZ1 and the PTN15-ALK signaling pathways represent potentially important therapeutic targets for glioblastoma invasion and growth.
Lu
Kan V
KV
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
Jong
Kimberly A
KA
Kim
Gloria Y
GY
Singh
Jatinder
J
Dia
Ederlyn Q
EQ
Yoshimoto
Koji
K
Wang
Maria Y
MY
Cloughesy
Timothy F
TF
Nelson
Stanley F
SF
Mischel
Paul S
PS
D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D005909:Glioblastoma / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D009363:Neoplasm Proteins / Q000032:analysis; D009414:Nerve Growth Factors / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000502:physiology; D011505:Protein-Tyrosine Kinases; D012334:RNA, Neoplasm / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D016207:Cytokines; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D012334:RNA, Neoplasm; C066845:pleiotrophin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C516895:PTPRZ1 protein, human; D017027:Protein Tyrosine Phosphatases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5