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The Role of LIM Proteins in Signal Transduction Susan Brown Department of Biochemistry and Molecular Biology, Monash University, Vic 3800

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The Role of LIM Proteins in Signal Transduction Susan Brown Department of Biochemistry and Molecular Biology, Monash University, Vic 3800 Volume 32, No. 1, April 2001 S h o w c a s e o n R e s e a r c h The Role of LIM Proteins in Signal Transduction Susan Brown Department of Biochemistry and Molecular Biology, Monash University, Vic 3800 The intricacy and diversity of cell func- The LIM domain is similar to, but dis- tifs, but have also been shown to bind pro- tions require an incredible complexity and tinct from, other zinc-binding motifs des- teins, mediating dimerisation and interac- specificity of protein interactions (1). LIM ignated zinc fingers, which occur in a wide tion with other zinc-finger and non-zinc domains are one of a growing number of variety of proteins (3). Zinc fingers were finger proteins. Evidence to date indicates structural motifs implicated in mediating initially recognised as DNA-binding mo- that LIM domains are protein-binding zinc protein-protein interactions required for regulation of transcription and mainte- nance of the actin cytoskeleton (2). This review will focus on the role of LIM pro- teins in cell signalling pathways. LIM is an acronym of three transcrip- tion factors lin-11, isl-1 and mec-3, in which the motif was first identified. LIM domains contain 50 - 60 amino acids form- ing a double zinc-finger motif with the consensus sequence (C-X2-C-X16-23-H- X2-C)-X2-(C-X2-C-X16-21-C-X2-H/D/C) (Fig. 1). The conserved cysteine, histidine and aspartic acid residues form two tetrahe- dral zinc-binding pockets, which stabilize the secondary and tertiary structure of the Fig. 1. Schematic representation of a LIM domain. The highly conserved cysteine (C) and histidine (H) amino acids form two zinc-binding pockets. The two zinc fingers are always separated by two amino protein. Mutation of either the conserved acids. The more variable sequences of between 16 and 23 amino acids form the two fingers and contain cysteine or histidine, disrupts both zinc the protein binding sites. binding and the function of the LIM domain. fingers (4). The presence of two or more LIM domains in most LIM proteins, ena- bles LIM proteins to bind more than one protein, and therefore to act as molecu- lar adaptors or scaffolds for the coordi- nated interaction of several proteins. LIM proteins have been divided into three groups according to the amino acid homology between their LIM domains, classified as types A-E (Fig. 2) (2). Group 1 LIM proteins contain paired N-termi- nal type A and B LIM domains either alone (Lmo proteins), or in association with a C-terminal homeodomain (LIM-homeo- domain proteins) or a kinase domain (LIM-kinase). Group 1 LIM proteins are predominantly nuclear, with the exception of LIM-kinase 1. LIM-homeodomain pro- teins perform critical roles in embryonic development and tissue differentiation. Group 2 LIM proteins contain one or two Type C LIM domains followed by a glycine-rich region with no other signifi- cant signalling domains. They include cysteine-rich protein 3/ muscle LIM pro- tein (CRP3/MLP), targeted deletion of which has been shown to cause a dilated 7 Australian Biochemist S h o w c a s e o n R e s e a r c h The Role of LIM Proteins in Signal Transduction (contin.) cardiomyopathy in mice (5). of transcription factors, to fine-tune gene cell line inhibits red cell maturation and The CRP family members have a joint expression, particularly of genes involved haemoglobinisation (9). Lmo2 might en- localisation in the nucleus and associated in tissue differentiation. able a population of early erythroid cells with the actin cytoskeleton. Group 3 LIM LIM proteins have been associated with to continue proliferating by inhibiting ter- proteins contain 1-5 predominantly C- both congenital and acquired human dis- minal differentiation. This may explain why terminal Type D and E LIM domains in eases. Mutations of the gene encoding the unregulated Lmo2 expression in T- association with other signalling domains LIM-homeodomain protein, Lmx1b, which lymphocytes causes leukaemia. such as PDZ or proline-rich motifs. regulates dorsal limb patterning, cause Group 3 LIM proteins are predominantly Nail-patella syndrome (6). Heterozygos- LIM proteins in cell signalling cytoplasmic, many interacting with the ity of the LIM-kinase1 gene is responsible Non-nuclear LIM proteins bind cyto- cytoskeleton. They include the important for the visual cognition defects occurring solic signalling and cytoskeletal proteins. focal adhesion proteins, paxillin and zyxin. in Williams syndrome (7). Lmo2, a nuclear In a manner analogous to transcription It has been proposed that LIM proteins, LIM protein containing only two LIM do- factor complexes, cytosolic LIM proteins which contain up to 5 LIM domains, form mains, is associated with the most com- enable the interaction of proteins impor- a scaffold upon which the coordinated mon translocations in T-cell acute lym- tant for signal transduction and regula- assembly of signalling proteins occurs (4). phoblastic leukaemia (T-ALL). Lmo2 is also tion of the cytoskeleton. In the cytoplasm, LIM-homeodomain proteins bind DNA essential for normal erythopoiesis; knock- LIM domain binding may regulate intrac- via their homeodomain, whilst their as- out mice die in utero due to severe anae- ellular localisation or link different signal- sociated LIM domains bind other protein mia (8). ling pathways. transcription factors. The LIM domain ap- The LIM domains of Lmo2 enable the For example, individual LIM domains of pears to have an inhibitory effect on the synergistic interaction of erythroid tran- PINCH, comprised of five LIM domains, associated homeodomain’s ability to bind scription factors. Although Lmo2 knock- bind integrin-linked kinase and the adap- DNA. Nuclear LIM-homeodomain and out mice fail to develop red cells, over- tor protein Nck-2, comprised of SH2 and LIM-only proteins regulate the interaction expression of Lmo2 in a proerythroblast SH3 domains (10). Nck-2, binds activated tyrosine kinase growth factor receptors such as the platelet-derived growth fac- tor (PDGF) receptor. PINCH is able to form a complex between ILK and Nck-2, and therefore links integrin and growth factor receptor signalling. LIM-domains do not appear to bind a single consensus sequence. Instead, a number of binding partners with no over- ? all common sequence or structural mo- tifs have been identified. The highly con- served cysteine and histidine confer the overall structure and stability of the do- mains but the intervening amino acids are more variable. These intervening amino acids deter- mine the protein binding specificity of the domain, thus explaining the wide range of binding partners. LIM domains have been shown to homodimerise and heterodimerise, and to bind various ty- rosine-containing sequences, PDZ do- mains, ankyrin type repeats, PKC isoforms and kinase domains. The factors influenc- ing LIM domain binding and the role of LIM-mediated interactions in signal trans- duction are starting to be elucidated. LIM-tyrosine motif binding Fig. 2. Classification of LIM proteins. Group 1 LIM proteins contain paired type A and B LIM domains either alone or in association with a homeodomain (labelled-HD) or PDZ and kinase domains . Phosphorylated tyrosine motifs are a Group 2 LIM proteins contain type C LIM domains followed by a glycine-rich region (labelled-G). Group 3 widely utilised signalling mechanism for LIM domains contain C-terminal type D and E LIM domains, in association with other signalling domains such as PDZ domains. mediating protein-protein interactions, binding both SH2 and PTB (phospho- 8 Volume 32, No. 1, April 2001 S h o w c a s e o n R e s e a r c h The Role of LIM Proteins in Signal Transduction (contin.) tyrosine binding) domains. Other tyro- As for the interaction with Ret, kinase lar to the LIM protein association, differ- sine-containing motifs, which do not re- activity and phosphorylation of the tyro- ent RACKs bind certain PKC isoforms. quire phosphorylation, have been shown sine motif are not required for LIM bind- However the association of PKC with to interact with LIM domains. ing. Wu and co-workers noted that the RACKs is altered by cell stimulation, Such interactions have been demon- LIM-binding sequence of Ret may also whereas the association with ENH is not. strated for the LIM protein Enigma, which form a tyrosine tight-turn because its se- LIM protein binding of PKC may stabilise contains an N-terminal PDZ domain and quence is similar to the endocytic se- the interaction between PKC and its an- three C-terminal LIM domains. LIM2 of quence of the LDL receptor which itself choring RACK protein. Enigma binds Ret (11) and LIM3 binds the forms a tight-turn (13). insulin receptor (12). The respective LIM A consensus tyrosine tight-turn se- LIM-serine/threonine kinases domains bind tyrosine-containing se- quence containing two copies of Asn-Asn- LIM domains have been shown to as- quences, which although similar, are not Ala-Tyr-Phe arranged in a helix-turn-he- sociate with other serine/threonine interchangeable. lix, which mediates receptor endocyto- kinases. For example, LIM1 of PINCH LIM2 of Enigma interacts with an Asn- sis, interacts with a broader range of LIM binds the ankyrin repeats of integrin- Lys-Leu-Tyr sequence at the C-terminus domains, possibly indicating a more gen- linked kinase (ILK), a serine/threonine ki- of the tyrosine kinase receptor Ret (11). eral interaction between specific LIM pro- nase, implicated in integrin signalling (10). Germline mutations which inactivate Ret teins and tyrosine tight-turn motifs. The LIM domains of the focal adhesion kinase cause Hirchsprung’s disease, result- protein paxillin bind a serine/threonine ing in defective parasympathetic innerva- LIM-Protein kinase C interaction kinase.
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