Heparin-binding proteins HB-GAM (pleiotrophin) and amphoterin in the regulation of cell motility.
Fractionation of proteins from perinatal rat brain was monitored using a neurite outgrowth assay. Two neurite-promoting proteins, HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin) and amphoterin, were isolated, cloned and produced by baculovirus expression for structural and functional studies. HB-GAM is highly expressed in embryonic and early post-natal fiber pathways of the nervous system, and it enhances axonal growth/guidance by binding to N-syndecan (syndecan-3) at the neuron surface. N-syndecan in turn communicates with the cytoskeleton through the cortactin/src-kinase pathway to enhance neurite extension. In addition to N-syndecan, the chondroitin sulfate proteoglycan RPTP beta/zeta (receptor-type tyrosine phosphatase beta/zeta) is implicated in the receptor mechanism of HB-GAM. HB-GAM is also prominently expressed in developing and regenerating bone as a matrix-bound cue for migration of osteoblasts/osteoblast precursors to the site of bone deposition. HB-GAM is suggested to regulate motility in osteoblasts through a similar mechanism as in neurons. Structural studies using heteronuclear NMR reveal two similar protein domains in HB-GAM, both consisting of three anti-parallel beta-strands. Search of sequence databases shows that the beta structures of HB-GAM and of the similar domains of MK (midkine) correspond to the thrombospondin type I (TSR) sequence motif. We suggest that the TSR sequence motif, found in several neurite outgrowth-promoting and other cell surface and matrix-binding proteins, defines a beta structure similar to those found in HB-GAM and MK. In general, amphoterin is highly expressed in immature and transformed cells. We suggest a model, according to which amphoterin is an autocrine/paracrine regulator of invasive migration. Amphoterin binds to RAGE (receptor of advanced glycation end products), an immunoglubulin superfamily member related to N-CAM (neural cell adhesion molecule), that communicates with the GTPases Cdc42 and Rac to regulate cell motility. In addition, ligation of RAGE by amphoterin activates NF-kappaB to regulate transcription.
Rauvala
H
H
Programme of Molecular Neurobiology, Institute of Biotechnology, and Department of Biosciences, University of Helsinki, Helsinki, Finland. heikki.rauvala@helsinki.fi
Huttunen
H J
HJ
Fages
C
C
Kaksonen
M
M
Kinnunen
T
T
Imai
S
S
Raulo
E
E
Kilpeläinen
I
I
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D003001:Cloning, Molecular; D016207:Cytokines / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology
D002352:Carrier Proteins; D016207:Cytokines; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins; D009419:Nerve Tissue Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C066845:pleiotrophin