ABSTRACT
Proteoglycans were first discovered in basement membranes by the presence of their sulfate esters and their ability to be detected with cationic dyes (1,2). The presence of heparan sulfate proteoglycans in basement membranes was observed by the sensitivity of cationic dye staining to treatment with heparitinase or nitrous acid (3). Since these initial studies, major efforts have concentrated on the isolation and purification of basement membrane proteoglycans. The EngelbrethHolm-Swarm (EHS) tumor, which produces other basement membrane molecules such as laminin and collagen IV, was the source used to first isolate a heparan sulfate proteoglycan in large quantities which was subsequently called large lowdensity heparan sulfate proteoglycan (4). Antibodies to this proteoglycan showed it was present in all basement membranes including all vascular basement membranes, as well as in many extracellular matrices, and showed the core protein to be 400 kD (5,6). The antibodies were also used to isolate the first cDNA clones (7) which provided the initial characterization of its core protein. This heparan sulfate proteoglycan (HSPG) was then named perlecan, referring to its rotary shadowed electron microscopy structure which appeared as ‘‘beads along a
string’’ (8). Perlecan is one of the most heavily studied proteoglycans, to date. For reviews see Refs. 9-14. This review will concentrate on the recent findings. Since perlecan is found in all basement membranes and many extracellular matrices, it has a wide range of regulatory controls, binding properties, and interactions. Perlecan’s gene structure is enormously complex and the promoter region has recently been characterized, thus providing a plethora of information about the regulatory control elements which determine the expression of this proteoglycan. Perlecan is not only regulated by cytokines but can also be bound to them, as well as to growth factors, with high affinity. Some of these interactions involve only perlecan’s heparan sulfate side chains, and others involve the core protein. Perlecan also appears to be an early response gene since several studies have reported rapid induction of perlecan expression. Perlecan can act as a growth stimulant for some cell types including cancer cells, and is a potent inhibitor of proliferation for others such as vascular smooth muscle cells. This proteoglycan can act as a coreceptor or prevent other molecules from interacting with theirs. In addition, perlecan has now been shown to bind most of the basement membrane components as well as several extracellular matrix molecules. Recent studies on the nematode perlecan gene have provided striking details on the role of perlecan in myofilament formation and organization as well as on how the basement membrane is formed. Perlecan also plays an important role in the development of pulmonary, intestinal, cartilaginous, muscular, cardiovascular, and organ maturation of mesenchymal tissues. It has recently been shown to have an active role in the pathogenesis of a wide range of diseases, including Alzheimer’s disease, Scrapie, diabetes, arteriosclerosis, and cancer; and it can be essential to tumor growth, involved in the sequestering of cytokines/growth factors, induction of angiogenesis for tumor blood supply, and in enhancing metastatic potential. Perlecan is even being targeted in the therapies for some of these diseases. Clearly, the ubiquitous expression of this proteoglycan and its potential diversity through alternative splicing and the attachment of either heparan sulfate or chondroitin sulfate or both types of side chains has led to many recent discoveries and many more are sure to follow.
