Laminins in Epithelial Cell Polarization:
Old Questions in Search of New Answers
Karl S. Matlin,1 Satu-Marja Myllymäki,2 and Aki Manninen2
1
Department of Surgery, The University of Chicago, Chicago, Illinois 60637-1470
2
Biocenter Oulu, Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine,
University of Oulu, Oulu 90220, Finland
Correspondence:
Laminin, a basement membrane protein discovered in 1979, was shortly thereafter impli-
cated in the polarization of epithelial cells in both mammals and a variety of lower organisms.
To transduce a spatial cue to the intrinsic polarization machinery, laminin must polymerize
into a dense network that forms the foundation of the basement membrane. Evidence sug-
gests that activation of the small GTPase Rac1 by b1-integrins mobilizes laminin-binding
integrins and dystroglycan to consolidate formation of the laminin network and initiate
rearrangements of both the actin and microtubule cytoskeleton to help establish the apico-
basal axis. A key coordinator of spatial signals from laminin is the serine –threonine kinase
Par-1, which is known to affect dystroglycan availability, microtubule and actin organization,
and lumen formation. The signaling protein integrin-linked kinase (ILK) may also play a role.
Despite significant advances, knowledge of the mechanism by which assembled laminin
produces a spatial signal remains fragmentary, and much more research into the complex
functions of laminin in polarization and other cellular processes is needed.
he evolution of epithelial cells made multi- the basement membrane to form a continuous,
T cellular organisms possible (Fahey and Deg-
nan 2010; Leys and Riesgo 2011). Epithelial
semipermeable cell layer or epithelium that
shares the polarity of the individual cellular
cells individually display a stable asymmetric constituents. This combination of collective
organization or polarity, defined by a plasma cell polarity and a barrier created by the epithe-
membrane differentiated into domains consist- lial layer divides multicellular organisms into
ing of a free or apical surface, a lateral surface, compartments with different chemical compo-
and a basal surface, each with a characteristic sitions and specialized functions, and separates
protein and lipid composition. Polarity extends the inner milieu from the outside world.
as well to the cytoplasm, with organelles ar- Polarization of epithelial cells occurs
ranged along an axis running from the apical through the cooperation of intrinsic and extrin-
to basal surface. Most significantly, epithelial sic polarization mechanisms (Nelson 2009).
cells adhere to each other laterally and to an The intrinsic mechanism depends on mutually
underlying extracellular matrix sheet known as antagonistic interactions among a series of cy-
Editor: Keith E. Mostov
Additional Perspectives on Cell Polarity available at www.cshperspectives.org
Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a027920
Cite this article as Cold Spring Harb Perspect Biol 2017;9:a027920
1
, K.S. Matlin et al.
toplasmic polarization signaling proteins com- we present experimental evidence supporting
monly divided into three groups called the Par, laminin’s role as an element of the extrinsic po-
Scribbled, and Crumbs complexes, and activa- larization mechanism. Along the way we will
tion of the small GTPases Rac1 and Cdc42 (Nel- highlight issues with experimental approaches
son 2009). The extrinsic polarization mecha- that have, in our estimation, limited progress in
nism, on the other hand, provides spatial this important area.
orientation cues to the cell from the environ-
ment, triggering the asymmetric distribution
and activation of the complexes that make up THE LAMININ FAMILY
the intrinsic mechanism. In early embryos, pri-
All bilaterians express laminins that have a ca-
mary spatial cues take a variety of forms. In
nonical heterotrimeric structure consisting of
Caenorhabditis elegans, for example, the sperm
a, b, and g subunits assembled into a cross-
entry point provides the cue, whereas in Dro-
shaped molecule (Fig. 1) (Miner and Yurchenco
sophila asymmetry is inherited epigenetically
2004; Fahey and Degnan 2012). The amino-ter-
through the process of oogenesis (Deng and
minal parts of each subunit form the three arms
Ruohola-Baker 2000; Dawes and Munro 2011;
Thompson 2012). In many, if not most, other
cases involving polarization of epithelial cells, α1 CollV
either initially during development or in adults Polym.
(sulfatide)
following injuries that disrupt polarity, there is LN Perl
evidence that cell adhesion to both other cells LEa
Nd1
and to the basement membrane (BM) protein L4a
laminin provide spatial cues. Polym. Polym.
Laminin was discovered by Rupert Timpl in LEb
LEa LEa
1979 during biochemical analysis of a matrix- LN L4b L4a LN
LF
like material secreted by the EHS mouse sar- β1 γ1
coma (Timpl et al. 1979). When used for
immunohistochemistry, specific antibodies
against this protein showed that laminin is lo-
Coiled-coil
Agrin
calized in the BMs underlying epithelia and sur-
rounding nerves and muscle fibers. In the 1980s,
Peter Ekblom implicated laminin in the differ-
entiation and polarization of the primordial
kidney epithelium from induced metanephric
mesenchyme in the mouse (Ekblom et al. LG
α6β1 1 3
1980; Klein et al. 1988). Since then, further re- α6β4 2 αDG,
α7β1 5 4 sulfatides
search in mammals and lower organisms has (SGL) HS
consistently supported the idea that laminin fa-
cilitates epithelial polarization. How laminin Figure 1. The structure of a canonical laminin mole-
accomplishes this remains, however, unclear. cule, using Lm111 as an example. Note the three
In this article, we review the evidence that laminin amino-terminal (LN) or polymerization do-
laminin plays a critical role in the polarization of mains on the a1, b1, and g1 subunits, and the lam-
epithelial cells. We first describe the complex inin globular (LG) domains on the carboxyl terminus
laminin family and how laminins contribute of the a1 subunit. The binding sites of integrins,
to the assembly and overall structure of the a-dystroglycan (aDG), and sulfated glycolipids
(SGLs) as well heparan sulfates to LG domains are
BM. We then focus on laminin receptors ex- indicated. Nd1 refers to the binding site of nidogen, a
pressed in epithelial cells, including both inte- protein that cross-links collagen type IV (CollIV) to
grins and dystroglycan, and on their atypical laminin. (From Yurchenco 2015; reprinted, with per-
distributions and functions in epithelia. Finally, mission, from Elsevier # 2015.)
2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a027920
Old Questions in Search of New Answers
Karl S. Matlin,1 Satu-Marja Myllymäki,2 and Aki Manninen2
1
Department of Surgery, The University of Chicago, Chicago, Illinois 60637-1470
2
Biocenter Oulu, Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine,
University of Oulu, Oulu 90220, Finland
Correspondence:
Laminin, a basement membrane protein discovered in 1979, was shortly thereafter impli-
cated in the polarization of epithelial cells in both mammals and a variety of lower organisms.
To transduce a spatial cue to the intrinsic polarization machinery, laminin must polymerize
into a dense network that forms the foundation of the basement membrane. Evidence sug-
gests that activation of the small GTPase Rac1 by b1-integrins mobilizes laminin-binding
integrins and dystroglycan to consolidate formation of the laminin network and initiate
rearrangements of both the actin and microtubule cytoskeleton to help establish the apico-
basal axis. A key coordinator of spatial signals from laminin is the serine –threonine kinase
Par-1, which is known to affect dystroglycan availability, microtubule and actin organization,
and lumen formation. The signaling protein integrin-linked kinase (ILK) may also play a role.
Despite significant advances, knowledge of the mechanism by which assembled laminin
produces a spatial signal remains fragmentary, and much more research into the complex
functions of laminin in polarization and other cellular processes is needed.
he evolution of epithelial cells made multi- the basement membrane to form a continuous,
T cellular organisms possible (Fahey and Deg-
nan 2010; Leys and Riesgo 2011). Epithelial
semipermeable cell layer or epithelium that
shares the polarity of the individual cellular
cells individually display a stable asymmetric constituents. This combination of collective
organization or polarity, defined by a plasma cell polarity and a barrier created by the epithe-
membrane differentiated into domains consist- lial layer divides multicellular organisms into
ing of a free or apical surface, a lateral surface, compartments with different chemical compo-
and a basal surface, each with a characteristic sitions and specialized functions, and separates
protein and lipid composition. Polarity extends the inner milieu from the outside world.
as well to the cytoplasm, with organelles ar- Polarization of epithelial cells occurs
ranged along an axis running from the apical through the cooperation of intrinsic and extrin-
to basal surface. Most significantly, epithelial sic polarization mechanisms (Nelson 2009).
cells adhere to each other laterally and to an The intrinsic mechanism depends on mutually
underlying extracellular matrix sheet known as antagonistic interactions among a series of cy-
Editor: Keith E. Mostov
Additional Perspectives on Cell Polarity available at www.cshperspectives.org
Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a027920
Cite this article as Cold Spring Harb Perspect Biol 2017;9:a027920
1
, K.S. Matlin et al.
toplasmic polarization signaling proteins com- we present experimental evidence supporting
monly divided into three groups called the Par, laminin’s role as an element of the extrinsic po-
Scribbled, and Crumbs complexes, and activa- larization mechanism. Along the way we will
tion of the small GTPases Rac1 and Cdc42 (Nel- highlight issues with experimental approaches
son 2009). The extrinsic polarization mecha- that have, in our estimation, limited progress in
nism, on the other hand, provides spatial this important area.
orientation cues to the cell from the environ-
ment, triggering the asymmetric distribution
and activation of the complexes that make up THE LAMININ FAMILY
the intrinsic mechanism. In early embryos, pri-
All bilaterians express laminins that have a ca-
mary spatial cues take a variety of forms. In
nonical heterotrimeric structure consisting of
Caenorhabditis elegans, for example, the sperm
a, b, and g subunits assembled into a cross-
entry point provides the cue, whereas in Dro-
shaped molecule (Fig. 1) (Miner and Yurchenco
sophila asymmetry is inherited epigenetically
2004; Fahey and Degnan 2012). The amino-ter-
through the process of oogenesis (Deng and
minal parts of each subunit form the three arms
Ruohola-Baker 2000; Dawes and Munro 2011;
Thompson 2012). In many, if not most, other
cases involving polarization of epithelial cells, α1 CollV
either initially during development or in adults Polym.
(sulfatide)
following injuries that disrupt polarity, there is LN Perl
evidence that cell adhesion to both other cells LEa
Nd1
and to the basement membrane (BM) protein L4a
laminin provide spatial cues. Polym. Polym.
Laminin was discovered by Rupert Timpl in LEb
LEa LEa
1979 during biochemical analysis of a matrix- LN L4b L4a LN
LF
like material secreted by the EHS mouse sar- β1 γ1
coma (Timpl et al. 1979). When used for
immunohistochemistry, specific antibodies
against this protein showed that laminin is lo-
Coiled-coil
Agrin
calized in the BMs underlying epithelia and sur-
rounding nerves and muscle fibers. In the 1980s,
Peter Ekblom implicated laminin in the differ-
entiation and polarization of the primordial
kidney epithelium from induced metanephric
mesenchyme in the mouse (Ekblom et al. LG
α6β1 1 3
1980; Klein et al. 1988). Since then, further re- α6β4 2 αDG,
α7β1 5 4 sulfatides
search in mammals and lower organisms has (SGL) HS
consistently supported the idea that laminin fa-
cilitates epithelial polarization. How laminin Figure 1. The structure of a canonical laminin mole-
accomplishes this remains, however, unclear. cule, using Lm111 as an example. Note the three
In this article, we review the evidence that laminin amino-terminal (LN) or polymerization do-
laminin plays a critical role in the polarization of mains on the a1, b1, and g1 subunits, and the lam-
epithelial cells. We first describe the complex inin globular (LG) domains on the carboxyl terminus
laminin family and how laminins contribute of the a1 subunit. The binding sites of integrins,
to the assembly and overall structure of the a-dystroglycan (aDG), and sulfated glycolipids
(SGLs) as well heparan sulfates to LG domains are
BM. We then focus on laminin receptors ex- indicated. Nd1 refers to the binding site of nidogen, a
pressed in epithelial cells, including both inte- protein that cross-links collagen type IV (CollIV) to
grins and dystroglycan, and on their atypical laminin. (From Yurchenco 2015; reprinted, with per-
distributions and functions in epithelia. Finally, mission, from Elsevier # 2015.)
2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a027920
